Peptide/particle delivery systems

ABSTRACT

Polymeric nanoparticles, microparticles, and gels for delivering cargo, e.g., a therapeutic agent, such as a peptide, to a target, e.g., a cell, and their use for treating diseases, including angiogenesis-dependent diseases, such as age-related macular degeneration and cancer, are disclosed. Methods for formulating, stabilizing, and administering single peptides or combinations of peptides via polymeric particle and gel delivery systems also are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No. 16/860,773, filed Apr. 28, 2020, which is a continuation of U.S. patent application Ser. No. 15/645,337, filed Jul. 10, 2017 and issued Sep. 29, 2020 as U.S. Pat. No. 10,786,463, which is a U.S. patent application Ser. No. 13/272,042, filed Oct. 12, 2011 and issued Aug. 1, 2017 as U.S. Pat. No. 9,717,694. U.S. Ser. No. 13/272,042 is a continuation-in-part of and claims priority to PCT Application No. PCT/US2010/035127, filed May 17, 2010. PCT/US2010/035127 claims the benefit of U.S. Provisional Application No. 61/178,611, filed May 15, 2009. U.S. Ser. No. 13/272,042 also claims the benefit of U.S. Provisional Application Nos. 61/392,224, filed Oct. 12, 2010; 61/542,995, filed Oct. 4, 2011; and 61/543,046, filed Oct. 4, 2011. The contents of each of the above-identified applications is incorporated herein by reference in its entirety.

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under CA131931 and CA152473 awarded by the National Institutes of Health. The government has certain rights in the invention.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created a Jan. 14, 2021, is 371,000 bytes in size and is named 39187-308_SEQUENCE_LISTING.

BACKGROUND

Biomaterials have the potential to significantly impact medicine as delivery systems for imaging agents, biosensors, drugs, and genes. Farokhzad O C. Nanotechnology for drug delivery: the perfect partnership. Expert Opin Drug Deliv 2008; 5(9):927-9; Putnam D. Polymers for gene delivery across length scales. Nat Mater 2006; 5(6):439-51; Brigger I, Dubernet C, Couvreur P. Nanoparticles in cancer therapy and diagnosis. Adv Drug Deliv Rev 2002; 54(5):631-51. Challenges exist, however, in creating a delivery vehicle capable of effective, safe, and controlled release of sensitive biomolecules. Although rapid advances have been made for sustained delivery of small molecule drugs using biotechnology, similar advances have not been made for the delivery of peptides, siRNA, or combinations of biological agents.

SUMMARY

The presently disclosed subject matter provides polymeric nanoparticles, microparticles, and gels for delivering cargo, e.g., a therapeutic agent, such as a peptide, to a target, e.g., a cell, and their use for treating multiple diseases, including angiogenesis-dependent diseases, such as age-related macular degeneration and cancer. Methods for formulating, stabilizing, and administering single peptides or combinations of peptides via polymeric particle and gel delivery systems, for example, using a controlled release strategy, also are disclosed.

In some aspects, the presently disclosed subject matter provides a bioreducible, hydrolytically degradable polymer of formula (Ia):

wherein:

n is an integer from 1 to 10,000;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, and R₉ are each independently selected from the group consisting of hydrogen, branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, aryl, halogen, hydroxyl, alkoxy, carbamoyl, carboxyl ester, carbonyldioxyl, amide, thiohydroxyl, alkylthioether, amino, alkylamino, dialkylamino, trialkylamino, cyano, ureido, a substituted alkanoyl group, cyclic, cyclic aromatic, heterocyclic, and aromatic heterocyclic groups, each of which may be substituted with at least one substituent selected from the group consisting of branched or unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, amino, alkylamino, dialkylamino, trialkylamino, aryl, ureido, heterocyclic, aromatic heterocyclic, cyclic, aromatic cyclic, halogen, hydroxyl, alkoxy, cyano, amide, carbamoyl, carboxylic acid, ester, carbonyl, carbonyldioxyl, alkylthioether, and thiohydroxyl groups;

wherein R₁ can be present or absent and when present the compound of formula (I) further comprises a counter ion selected from the group consisting of chloride, fluoride, bromide, iodide, sulfate, nitrate, fumarate, acetate, carbonate, stearate, laurate, and oleate; and

wherein at least one R comprises a backbone of a diacrylate having the following structure:

wherein X₁ and X₂ are each independently substituted or unsubstituted C2-C20 alkylene, and wherein each X₁ and X2 can be the same or different.

In other aspects, the presently disclosed subject matter provides a nanoparticle, microparticle, or gel comprising a compound of formula (I):

wherein:

n is an integer from 1 to 10,000;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, and R₉ are each independently selected from the group consisting of hydrogen, branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, aryl, halogen, hydroxyl, alkoxy, carbamoyl, carboxyl ester, carbonyldioxyl, amide, thiohydroxyl, alkylthioether, amino, alkylamino, dialkylamino, trialkylamino, cyano, ureido, a substituted alkanoyl group, cyclic, cyclic aromatic, heterocyclic, and aromatic heterocyclic groups, each of which may be substituted with at least one substituent selected from the group consisting of branched or unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, amino, alkylamino, dialkylamino, trialkylamino, aryl, ureido, heterocyclic, aromatic heterocyclic, cyclic, aromatic cyclic, halogen, hydroxyl, alkoxy, cyano, amide, carbamoyl, carboxylic acid, ester, carbonyl, carbonyldioxyl, alkylthioether, and thiohydroxyl groups;

wherein R₁ can be present or absent and when present the compound of formula (I) further comprises a counter ion selected from the group consisting of chloride, fluoride, bromide, iodide, sulfate, nitrate, fumarate, acetate, carbonate, stearate, laurate, and oleate; and

at least one of R, R′, and R″ comprise a reducible or degradable linkage, and wherein each R, R′, or R″ can independently be the same or different;

under the proviso that when at least one R group comprises an ester linkage of the formula —C(═O)—O— and the compound of formula (I) comprises a poly(beta-amino ester), then the compound of formula (I) must also comprise one or more of the following characteristics:

(a) each R group is different;

(b) each R″ group is different;

(c) each R″ group is not the same as any of R′, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, and R₉;

(d) the R″ groups degrade through a different mechanism than the ester-containing R groups, wherein the degradation of the R″ group is selected from the group consisting of a bioreducible mechanism or an enzymatically degradable mechanism; and/or

(e) the compound of formula (I) comprises a substructure of a larger cross-linked polymer, wherein the larger cross-linked polymer comprises different properties from compound of formula (I);

and one or more peptides selected from the group consisting of an anti-angiogenic peptide, an anti-lymphangiogenic peptide, an anti-tumorigenic peptide, and an anti-permeability peptide.

In other aspects, the presently disclosed subject matter provides a multilayer particle comprising a core and one or more layers, wherein the core comprises a material selected from the group consisting of a compound of formula (I), a gold nanoparticle, an inorganic nanoparticle, an organic polymer, and the one or more layers comprise a material selected from the group consisting of a compound of formula (I), an organic polymer, one or more peptides, and one or more additional biological agents. In yet other aspects, the presently disclosed subject matter provides a microparticle comprising a compound of formula (I), poly(lactide-co-glycolide) (PLGA), or combinations thereof.

In other aspects, the presently disclosed subject matter provides a method for stabilizing a suspension of nanoparticles and/or microparticles of formula (I), the method comprising: (a) providing a suspension of nanoparticles and/or microparticles of formula (I); (b) admixing a lyroprotectant with the suspension; (c) freezing the suspension for a period of time; and (d) lyophilizing the suspension for a period of time.

In further aspects, the presently disclosed subject matter provides a pellet or scaffold comprising one or more lyophilized particle, wherein the one or more lyophilized particle comprises a compound of formula (I).

In yet further aspects, the presently disclosed subject matter provides a method of treating a disease or condition, the method comprising administering to a subject in need of treatment thereof a therapeutically effective amount of a nanoparticle, microparticle, gel, or multilayer particle comprising a compound of formula (I), wherein the nanoparticle, microparticle, gel, or multilayer particle further comprises a therapeutic agent specific for the disease or condition to be treated. In some aspects, the disease or condition comprises an angiogenesis-dependent disease or condition, including, but not limited to, cancer and age-related macular degeneration. In other aspects, the disease or condition is a non-angiogenic disease or condition. In certain aspects, the therapeutic agent encapsulated with the presently disclosed particles can be selected from the group consisting of gene, DNA, RNA, siRNA, miRNA, isRNA, agRNA, smRNA, a nucleic acid, a peptide, a protein, a chemotherapeutic agent, a hydrophobic drug, a small molecule drug, and combinations thereof.

Certain aspects of the presently disclosed subject matter having been stated hereinabove, which are addressed in whole or in part by the presently disclosed subject matter, other aspects will become evident as the description proceeds when taken in connection with the accompanying Examples and Figures as best described herein below.

BRIEF DESCRIPTION OF THE FIGURES

Having thus described the presently disclosed subject matter in general terms, reference will now be made to the accompanying Figures, which are not necessarily drawn to scale, and wherein:

FIG. 1 is an illustration of the presently disclosed multilayer particles;

FIG. 2 is a scheme for producing hydrogels comprising the presently disclosed materials.

FIG. 3 shows a scheme for producing stable nanoparticle suspensions;

FIG. 4A-FIG. 4D show representative polymer structures tuned to peptide cargos (FIG. 4A discloses SEQ ID NOs: 2485 and 2484, respectively, in order of appearance. FIG. 4B discloses SEQ ID NO: 2388. FIG. 4C discloses SEQ ID NO: 2483. FIG. 4D discloses SEQ ID NO: 2452.);

FIG. 5A and FIG. 5B show representative formation and sizing of polymer/peptide nanoparticles (by nanoparticle tracking analysis on a Nanosight LM10) (FIG. 5A discloses “DEAH” as SEQ ID NO: 2484);

FIG. 6 shows DEAH peptide (SEQ ID NO: 2484) release by 336 nanoparticles at 4° C. (above) and 37° C. (below);

FIG. 7 shows HUVEC viability/proliferation assays with polymer/SP6001/DEAH peptide (“DEAH” disclosed as SEQ ID NO: 2484);

FIG. 8 shows HUVEC migration assays with 336 polymer/DEAH peptide (“DEAH” disclosed as SEQ ID NO: 2484);

FIG. 9 shows in vivo 336 polymer nanoparticle/SP6001 DEAH peptide (“DEAH” disclosed as SEQ ID NO: 2484)’;

FIG. 10 shows (top) Particle size and (bottom) cell viability effects of various polymer/SP2012 nanoparticles as compared to peptide only of non-cytotoxic polymers;

FIG. 11 shows polymer/peptide formulations for alternative peptides;

FIG. 12 shows data for FITC-tagged bovine serum albumin (BSA) mixed with a macromer solution containing 10% (w/v) PEGDA (Mn-270 Da) with various amounts of B4S4, dissolved in a 1:1 (v/v) mixture of DMSO and PBS;

FIG. 13 shows an SEM of increasing B4S4 from top [0.2% w/w] to bottom [5% w/w]);

FIG. 14 shows the size distribution of appropriately freeze-dried particles (bottom left, right-most histogram) remains the same as freshly-prepared particles (bottom left, left-most histogram). Freeze-dried particles also remain more stable in serum-containing medium than freshly-prepared particles (upper left). Using DNA-loaded nanoparticles, transfection efficiency is comparable between fresh particles and particles lyophilized with sucrose (right) even after 3 months of storage;

FIG. 15 is Left: brightfield+GFP⁺ DsRed, showing presence of cells (green) being transfected with DsRed (red) on a bone scaffold (brightfield). Right: GFP and DsRed shown only;

FIG. 16 demonstrates that DsRed expression was observed within 4 days and remained very robust even after 12 days: top=1 day, middle=4 days, bottom=12 days after transfection;

FIG. 17 demonstrates the incorporation of DNA-loaded nanoparticles into natural and synthetic scaffolds, disks, microparticles, and hydrogels;

FIG. 18 demonstrates transfection of GFP⁺ glioblastoma cells with scrambled (control) siRNA (top panels) or siRNA against GFP (bottom);

FIG. 19A-FIG. 19C show activity of R6-series polymers at delivering siRNA to knockdown GFP signal in GB cells; % Knockdown of GFP expression in GFP+ glioblastoma cells transfected with siRNA against GFP, normalized to cells transfected with scrambled siRNA, using various BR6 polymers as a transfection agent: (FIG. 19A) transfection with acrylate-terminated BR6 polymers with either S3, S4 or S5 as the side chain; (FIG. 19B) transfection with E10 end-capped versions of the polymers in FIG. 19A; and (FIG. 19C) GFP fluorescence images of cells transfected with BR6-S4-Ac complexed scrambled RNA (top) vs. siRNA against GFP (bottom);

FIG. 20 shows gel retardation assay of siRNA with BR6-S5-E10 at varying ratios of polymer to RNA. The polymer effectively retards siRNA (top), but in the presence of 5 mM glutathione siRNA is released immediately (bottom). These data demonstrate the hypothesized intracellular release of siRNA and elucidates the mechanism by which nanoparticles formed using BR6 facilitate strong siRNA transfection and GFP knockdown;

FIG. 21 shows that an E10-endcapped polymer (top) retards siRNA efficiently, but upon addition of 5 mM glutathione, siRNA is immediately released (bottom). Numbers refer to the w/w ratio of polymer-to-siRNA in all cases;

FIG. 22 shows that the same base polymer as shown in FIG. 25 with a different endcap (E7, 1-(3-aminopropyl)-4-methylpiperazine) also retards siRNA (top) but is not affected by application of glutathione (bottom);

FIG. 23 provides gel permeation chromatography data of BR6 polymerized with S4 at a BR6:S4 ratio of 1.2:1 at 90° C. for 24 hours, before and after end-capping with E7;

FIG. 24 shows that knockdown efficiency also is affected by molecular weight of the polymer. 1.2:1, 1.1:1, and 1.05:1 refer to the ratio of reactants in the base polymer step growth reaction;

FIG. 25 demonstrates combined DNA (RFP) and siRNA delivery (against GFP) in GB;

FIG. 26 shows that siRNA knockdown is affected by the endcap (E), base polymer (increasing hydrophobicity from L to R within each E), and molecular weight (increasing L to R within each base polymer);

FIG. 27 shows 4410, 200 w/w (blue line on above graph), 8 days after transfection: Left: hMSCs treated with scrambled control; Right: hMSCs treated with siRNA;

FIG. 28 demonstrates that in variable molecular weight embodiments, polymer molecular weight is between 4.00-10.00 kDa for siRNA delivery;

FIG. 29 demonstrates the use of the presently disclosed materials for DNA delivery;

FIG. 30 shows GB Transfection;

FIG. 31 shows 551 GB cells cultured as neurospheres (undifferentiated);

FIG. 32 demonstrates that, for a DNA delivery application, in some embodiments, polymer molecular weight is between 3.00-10.0 kDa;

FIG. 33 provides representative characteristics exhibited by the presently disclosed biodegradable polymers;

FIG. 34 demonstrates the delivery of DNA to GB bulk tumor cells for representative biomaterials;

FIG. 35 demonstrates the transfection of genes to BCSC for representative presently disclosed biomaterials;

FIG. 36 demonstrates the delivery of DNA to fetal (healthy) cells;

FIG. 37 demonstrates the delivery of DNA to BCSCs;

FIG. 38 demonstrates the delivery of apoptosis-inducing genes in BCSCs;

FIG. 39 demonstrates the delivery of apoptosis-inducing genes in BCSCs;

FIG. 40 shows that particles lyophilized with sucrose and used immediately are as effective in transfection as freshly prepared particles;

FIG. 41 demonstrates the use of the presently disclosed materials and methods for long-term gene delivery;

FIG. 42 demonstrates the use of the presently disclosed materials and methods for long-term gene delivery;

FIG. 43 demonstrates siRNA delivery to GB cells;

FIG. 44 provides a comparison of siRNA vs. DNA delivery in GB cells;

FIG. 45 provides a comparison of siRNA vs. DNA delivery in GB cells;

FIG. 46 depicts a strategy of combining nanoparticles within microparticles to extend release further. PLGA or blends of PLGA with the presently disclosed polymers are used to form microparticles by single or double emulsion;

FIG. 47 shows DEAH-FITC release from microparticles comprising a presently disclosed polymer and a peptide (“DEAH” disclosed as SEQ ID NO: 2484);

FIG. 48 shows slow extended release from microparticles containing nanoparticles that contain peptides; and

FIG. 49A-FIG. 49C show in vivo effects of microparticle formulations in both the CNV and rho/VEGF model over time.

DETAILED DESCRIPTION

The presently disclosed subject matter now will be described more fully hereinafter with reference to the accompanying Figures, in which some, but not all embodiments of the inventions are shown. Like numbers refer to like elements throughout. The presently disclosed subject matter may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. Indeed, many modifications and other embodiments of the presently disclosed subject matter set forth herein will come to mind to one skilled in the art to which the presently disclosed subject matter pertains having the benefit of the teachings presented in the foregoing descriptions and the associated Figures. Therefore, it is to be understood that the presently disclosed subject matter is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims.

I. Peptide/Particle Delivery Systems

The presently disclosed subject matter provides compositions of matter, methods of formulation, and methods of treatment utilizing drug delivery systems comprising one or more degradable polymers and one or more biological agents. The polymers described in these systems must be biodegradable. Mechanisms for this degradability include, but are not limited to, hydrolytic degradation, enzymatic degradation, and disulfide reduction. The biological agents described in these systems include, but are not limited to, therapeutic or diagnostic agents, such as small molecules, peptides, proteins, DNA, siRNA, miRNA, isRNA, contrast agents, and other agents one skilled in the field would wish to encapsulate. In particular embodiments, biological therapeutic agents that are sensitive to degradation and sized approximately 10,000-25,000 Da, including siRNA and peptides, are suitable for use with the presently disclosed materials.

Peptide drugs in polymeric delivery systems are useful for various therapeutic and diagnostic applications. Some embodiments of the presently disclosed subject matter are useful for treating angiogenesis-dependent diseases including, but not limited to, age-related macular degeneration (AMD) and cancer. One particular embodiment of the presently disclosed subject matter includes specific peptide sequences, as well as methods of formulating, stabilizing, and administering these peptides as single agents or as combinations of peptides via polymeric nanoparticle-based, microparticle-based, gel-based, or conjugate-based delivery systems.

The presently disclosed nanoparticles, microparticles, and gels can be used to deliver cargo, for example a therapeutic agent, such as a peptide or protein, to a target, for example, a cell. The cargo delivered by the presently disclosed nanoparticles, microparticles, and gels can act, in some embodiments, as a therapeutic agent or a biosensor agent. Combinations of polymeric materials and cargo, for example a single peptide or combination of peptides, can be formulated by the presently disclosed methods, which allows for the control, or tuning, of the time scale for delivery.

Further, the presently disclosed polymeric materials can be used to form self-assembled electrostatic complexes, micelles, polymersomes, emulsion-based particles, and other particle formulations known to one of ordinary skill in the art. Nanoparticles formed from the presently disclosed polymeric materials can be formulated into larger microparticles to further extend duration and timing of release. Lyophilized formulations that can maintain longer shelf life and stability also are described. The presently disclosed particles can be administered as a powder, cream, ointment, implant, or other reservoir device.

The presently disclosed nanoparticles, microparticles, and gels can be used to treat many diseases and conditions including, but not limited to, all types of cancers, ophthalmic diseases, cardiovascular diseases, and the like. In particular embodiments, the disease or condition treated by the presently disclosed nanoparticles, microparticles, and gels include breast cancer and age-related macular degeneration.

A. Bioreducible and Hydrolytically Degradable Two-Component Degradable Polymers

The presently disclosed materials offer several advantages for use in delivering cargo, e.g., a therapeutic agent, such as a peptide or siRNA, to a target, e.g., a cell. Such advantages include a slower degradation in the extracellular environment and a quicker degradation in the intracellular environment. Further, the method of synthesis allows for diversity of monomer starting materials and corresponding facile permutations of polymer structure. The presently disclosed materials can be used to form self-assembled nanoparticles, blended microparticles, gels, and bioconjugates. The presently disclosed polymers also have the following advantages compared to other drug delivery polymers known in the art: a higher polymerization than with disulfide acrylamides, which is important for various applications because it can be used to tune both binding/encapsulation and release; two time scales for degradation (hydrolytic degradation in water and disulfide reduction due to glutathione inside the cell), which facilitates drug release and reduces potential cytotoxicity; tunable structural diversity, with hydrophobic, hydrophilic, and charged moieties to aid in encapsulation of a target biological agent; and, usefulness for drug delivery, including high siRNA delivery, even without end-modification of the polymer.

Certain polyesters have been shown previously to form nanoparticles in the presence of biological agents, such as nucleic acids, and facilitate their entry into a cell. In such materials, release of the nucleic acid is modulated by hydrolytic degradation of the polyester polymer. The addition of a bioreducible disulfide moiety into the backbone of these polymers, however, can specifically target release to the reducing intracellular environment.

Accordingly, a library of bioreducible polyesters can be synthesized by oxidizing and acrylating various mercapto-alcohols (representative diacrylates formed from the presently disclosed synthetic process are shown in Scheme 1 below), then reacting with amine side chains. The structure of a representative bioreducible polyester, e.g., 2,2′-disulfanediylbis(ethane-2,1-diyl) diacrylate (BR6) polymerized with S4, also is shown in Scheme 1.

In other embodiments, amine-containing molecules can be reacted to terminal groups of the polymer. In particular embodiments, this amine-containing molecule also contains poly(ethylene glycol) (PEG) or a targeting ligand. In other embodiments, the disulfide acrylates are not reacted with amines, but are instead polymerized through other mechanisms including, but not limited to, free radical polymerization to form network polymers and gels. In other embodiments, oligomers are first formed and then the oligomers are polymerized to form block co-polymers or gels.

More particularly, the presently disclosed subject matter provides a bioreducible, hydrolytically degradable polymer of formula (Ia):

wherein:

n is an integer from 1 to 10,000;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, and R₉ are each independently selected from the group consisting of hydrogen, branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, aryl, halogen, hydroxyl, alkoxy, carbamoyl, carboxyl ester, carbonyldioxyl, amide, thiohydroxyl, alkylthioether, amino, alkylamino, dialkylamino, trialkylamino, cyano, ureido, a substituted alkanoyl group, cyclic, cyclic aromatic, heterocyclic, and aromatic heterocyclic groups, each of which may be substituted with at least one substituent selected from the group consisting of branched or unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, amino, alkylamino, dialkylamino, trialkylamino, aryl, ureido, heterocyclic, aromatic heterocyclic, cyclic, aromatic cyclic, halogen, hydroxyl, alkoxy, cyano, amide, carbamoyl, carboxylic acid, ester, carbonyl, carbonyldioxyl, alkylthioether, and thiohydroxyl groups;

wherein R₁ can be present or absent and when present the compound of formula (I) further comprises a counter ion selected from the group consisting of chloride, fluoride, bromide, iodide, sulfate, nitrate, fumarate, acetate, carbonate, stearate, laurate, and oleate; and

wherein at least one R comprises a backbone of a diacrylate having the following structure:

wherein X₁ and X₂ are each independently substituted or unsubstituted C2-C20 alkylene, and wherein each X₁ and X₂ can be the same or different.

In some embodiments, the bioreducible, hydrolytically degradable polymer of claim 1, wherein at least one R comprises a backbone of a diacrylate selected from the group consisting of:

or co-oligomers comprising combinations thereof, wherein the diacrylate can be the same or different.

Additional R, R′, and R″ groups are defined immediately herein below as for compounds disclosed in International PCT Patent Application Publication No. WO/2010/132879 for “Multicomponent Degradable Cationic Polymers,” to Green et al., which is incorporated herein by reference in its entirety.

B. Hydrolytic and Bioreducible Polymeric Particle Formulations for Delivery of Peptides.

Multicomponent degradable cationic polymers suitable for the delivery of peptides to a target are disclosed in International PCT Patent Application Publication No. WO/2010/132879 for “Multicomponent Degradable Cationic Polymers,” to Green et al., which is incorporated herein by reference in its entirety. Such polymers, in addition to the presently disclosed polymers can be used to deliver cargo, e.g., a therapeutic agent, to a target, e.g., a cell.

In some embodiments, the presently disclosed subject matter generally provides multicomponent degradable cationic polymers. In some embodiments, the presently disclosed polymers have the property of biphasic degradation. Modifications to the polymer structure can result in a change in the release of therapeutic agents, which can occur over multiple time scales. In some embodiments, the presently disclosed polymers include a minority structure, e.g., an endcapping group, which differs from the majority structure comprising most of the polymer backbone. In other embodiments, the bioreducible oligomers form block copolymers with hydrolytically degradable oligomers. In yet other embodiments, the end group/minority structure comprises an amino acid or chain of amino acids, while the backbone degrades hydrolytically and/or is bioreducible.

As described in more detail herein below, small changes in the monomer ratio used during polymerization, in combination with modifications to the chemical structure of the end-capping groups used post-polymerization, can affect the efficacy of delivery of a therapeutic agent to a target. Further, changes in the chemical structure of the polymer, either in the backbone of the polymer or end-capping groups, or both, can change the efficacy of target delivery to a cell. In some embodiments, small changes to the molecular weight of the polymer or changes to the endcapping groups of the polymer, while leaving the main chain, i.e., backbone, of the polymer the same, can enhance or decrease the overall delivery of the target to a cell. Further, the “R” groups that comprise the backbone or main chain of the polymer can be selected to degrade via different biodegradation mechanisms within the same polymer molecule. Such mechanisms include, but are not limited to, hydrolytic, bioreducible, enzymatic, and/or other modes of degradation.

In some embodiments, the presently disclosed compositions can be prepared according to Scheme 2:

In some embodiments, at least one of the following groups R, R′, and R″ contain reducible linkages and, for many of the presently disclosed materials, additional modes of degradation also are present. More generally, R′ can be any group that facilitates solubility in water and/or hydrogen bonding, for example, OH, NH₂ and SH. Representative degradable linkages include, but are not limited to:

The end group structures, i.e., R″ groups in Scheme 2, for the presently disclosed cationic polymers are distinct and separate from the backbone structures (R) structures, the side chain structures (R′), and end group structures of the intermediate precursor molecule for a given polymeric material.

More particularly, in some embodiments, the presently disclosed subject matter includes a nanoparticle, microparticle, or gel comprising a compound of formula (I):

wherein:

n is an integer from 1 to 10,000;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, and R₉ are each independently selected from the group consisting of hydrogen, branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, aryl, halogen, hydroxyl, alkoxy, carbamoyl, carboxyl ester, carbonyldioxyl, amide, thiohydroxyl, alkylthioether, amino, alkylamino, dialkylamino, trialkylamino, cyano, ureido, a substituted alkanoyl group, cyclic, cyclic aromatic, heterocyclic, and aromatic heterocyclic groups, each of which may be substituted with at least one substituent selected from the group consisting of branched or unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, amino, alkylamino, dialkylamino, trialkylamino, aryl, ureido, heterocyclic, aromatic heterocyclic, cyclic, aromatic cyclic, halogen, hydroxyl, alkoxy, cyano, amide, carbamoyl, carboxylic acid, ester, carbonyl, carbonyldioxyl, alkylthioether, and thiohydroxyl groups;

wherein R₁ can be present or absent and when present the compound of formula (I) further comprises a counter ion selected from the group consisting of chloride, fluoride, bromide, iodide, sulfate, nitrate, fumarate, acetate, carbonate, stearate, laurate, and oleate; and

at least one of R, R′, and R″ comprise a reducible or degradable linkage, and wherein each R, R′, or R″ can independently be the same or different;

under the proviso that when at least one R group comprises an ester linkage of the formula —C(═O)—O— and the compound of formula (I) comprises a poly(beta-amino ester), then the compound of formula (I) must also comprise one or more of the following characteristics:

(a) each R group is different;

(b) each R″ group is different;

(c) each R″ group is not the same as any of R′, R₁, R₂, R₃, R₄, R₅, R, R₇, R₈, and R₉;

(d) the R″ groups degrade through a different mechanism than the ester-containing R groups, wherein the degradation of the R″ group is selected from the group consisting of a bioreducible mechanism or an enzymatically degradable mechanism; and/or

(e) the compound of formula (I) comprises a substructure of a larger cross-linked polymer, wherein the larger cross-linked polymer comprises different properties from compound of formula (I);

and one or more peptides selected from the group consisting of an anti-angiogenic peptide, an anti-lymphangiogenic peptide, an anti-tumorigenic peptide, and an anti-permeability peptide.

In some embodiments of the nanoparticle, microparticle, or gel n is an integer from 1 to 1,000; in some embodiments, n is an integer from 1 to 100; in some embodiments, n is an integer from 1 to 30; in some embodiments, n is an integer from 5 to 20; in some embodiments, n is an integer from 10 to 15; and in some embodiments, n is an integer from 1 to 10.

In particular embodiments, the reducible or degradable linkage comprising R, R′, and R″ is selected from the group consisting of an ester, a disulfide, an amide, an anhydride or a linkage susceptible to enzymatic degradation, subject to the proviso provided hereinabove.

In more particular embodiments, R comprises a backbone of a diacrylate selected from the group consisting of:

In some embodiments, wherein R′ comprises a side chain derived from compound selected from the group consisting of

In some embodiments, R″ comprises an end group derived from a compound selected from the group consisting of

In other embodiments, the compound of formula (I) is subject to the further proviso that if at least one R group comprises an ester linkage, then the R″ groups impart one or more of the following characteristics to the compound of formula (I): independent control of cell-specific uptake and/or intracellular delivery of a particle; independent control of endosomal buffering and endosomal escape; independent control of DNA release; triggered release of an active agent; modification of a particle surface charge; increased diffusion through a cytoplasm of a cell; increased active transport through a cytoplasm of a cell; increased nuclear import within a cell; increased transcription of an associated DNA within a cell; increased translation of an associated DNA within a cell; increased persistence of an associated therapeutic agent within a cell, wherein the therapeutic agent is selected from the group consisting of DNA, RNA, a peptide or a protein.

More particularly, any poly(beta-amino ester) specifically disclosed or claimed in U.S. Pat. Nos. 6,998,115; 7,427,394; U.S. patent application publication no. US2005/0265961; and U.S. patent publication no. US2010/0036084, each of which is incorporated herein by reference in its entirety, is explicitly excluded from the presently disclosed compounds of formula (I). In particular, the poly(beta-amino ester)s disclosed in U.S. Pat. Nos. 6,998,115; 7,427,394; U.S. patent application publication no. US2005/0265961; and U.S. patent publication no. US2010/0036084 are symmetrical, i.e., both R groups as defined in formula (I) herein are the same. In certain embodiments of the presently disclosed compounds of formula (I), when at least one R comprises an ester linkage, the two R groups of formula (I) are not the same, i.e., in such embodiments, the compounds of formula (I) are not symmetrical.

In particular embodiments, the reducible or degradable linkage comprising R, R′, and R″ is selected from the group consisting of an ester, a disulfide, an amide, an anhydride or a linkage susceptible to enzymatic degradation, subject to the above-mentioned provisos.

Further, in some embodiments of the compound of formula (I), n is an integer from 1 to 1,000; in other embodiments, n is an integer from 1 to 100; in other embodiments, n is an integer from 1 to 30; in other embodiments, n is an integer from 5 to 20; in other embodiments, n is an integer from 10 to 15; and in other embodiments, n is an integer from 1 to 10.

In some embodiments, R″ can be an oligomer as described herein, e.g., one fully synthesized primary amine-terminated oligomer, and can be used as a reagent during the second reaction step of Scheme 2. This process can be repeated iteratively to synthesize increasingly complex molecules.

In other embodiments, R″ can comprise a larger biomolecule including, but not limited to, poly(ethyleneglycol) (PEG), a targeting ligand, including, but not limited to, a sugar, a small molecule, an antibody, an antibody fragment, a peptide sequence, or other targeting moiety known to one skilled in the art; a labeling molecule including, but not limited to, a small molecule, a quantum dot, a nanoparticle, a fluorescent molecule, a luminescent molecule, a contrast agent, and the like; and a branched or unbranched, substituted or unsubstituted alkyl chain.

In some embodiments, the branched or unbranched, substituted or unsubstituted alkyl chain is about 2 to about 5 carbons long; in some embodiments, the alkyl chain is about 6 to about 8 carbons long; in some embodiments, the alkyl chain is about 9 to about 12 carbons long; in some embodiments, the alkyl chain is about 13 to about 18 carbons long; in some embodiments, the alkyl chain is about 19 to about 30 carbons long; in some embodiments, the alkyl chain is greater than about 30 carbons long.

In certain embodiments, both R″ groups, i.e., the end groups of the polymer, comprise alkyl chains. In other embodiments, only one R″ group comprises an alkyl chain. In some embodiments, at least one alkyl chain is terminated with an amino (NH₂) group. In other embodiments, the at least one alkyl chain is terminated with a hydroxyl (OH) group.

In some embodiments, the PEG has a molecular weight of about 5 kDa or less; in some embodiments, the PEG has a molecular weight of about 5 kDa to about 10 kDa; in some embodiments, the PEG has a molecular weight of about 10 kDa to about 20 kDa; in some embodiments, the PEG has a molecular weight of about 20 kDa to about 30 kDa; in some embodiments, the PEG is greater than 30 kDa. In certain embodiments, both R″ groups comprise PEG. In other embodiments, only one R″ group comprises PEG.

Further, in some embodiments, one R″ group is PEG and the other R″ group is a targeting ligand and/or labeling molecule as defined herein above. In other embodiments, one R″ group is an alkyl chain and the other R″ group is a targeting ligand and/or labeling molecule.

Representative monomers used to synthesize the presently disclosed cationic polymers include, but are not limited to, those provided immediately herein below. The presently disclosed subject matter is not limited to the representative monomers disclosed herein, but also includes other structures that one skilled in the art could use to create similar biphasic degrading cationic polymers. For each type of cargo, a particular biodegradable polymer can be tuned through varying the constituent monomers used to form the backbone (designated as “B” groups), side-chains (designated as “S” groups), and end-groups (designated as “E” groups) of the polymer.

In particular embodiments, as depicted in Scheme 4, the presently disclosed cationic polymers comprise a polyalcohol structure, i.e., the side chain represented by R′ in Scheme 2 comprises an alcohol.

In such embodiments, the end group structures (R″) and the backbone structures (R) are defined as above and the side chain must contain at least one hydroxyl (OH) group.

In yet other embodiments, the presently disclosed cationic polymer comprises a specific poly(ester amine) structure with secondary non-hydrolytic modes of degradation. In such embodiments, the cationic polymer comprises a polyester that degrades through ester linkages (hydrolytic degradation) that is further modified to comprise bioreducible groups as end (R″) groups.

Representative bioreducible end groups in such embodiments include, but are not limited to:

In some embodiments, the presently disclosed cationic polymer comprises a specific poly(ester amine alcohol) structure with secondary non-hydrolytic modes of degradation. In such embodiments, the cationic polymer comprises a specific structure where a polyester that degrades through ester linkages (hydrolytic degradation) is modified to contain bioreducible groups as end groups.

In yet other embodiments, the presently disclosed cationic polymer comprises a specific poly(amido amine) structure having disulfide linking groups in the polymer backbone and an independent, non-reducible amine contacting group at the terminal ends of the polymer.

In such embodiments, R₁ and R₂ are alkyl chains. In some embodiments, the alkyl chain is 1-2 carbons long; in some embodiments, the alkyl chain is 3-5 carbons long; in some embodiments, the alkyl chain is 6-8 carbons long; in some embodiments, the alkyl chain is 9-12 carbons long; in some embodiments, the alkyl chain is 13-18 carbons long; in some embodiments, the alkyl chain is 19-30 carbons long; and in some embodiments, the alkyl chain is greater than 30 carbons long

Suitable non-reducible amino R″ groups for such embodiments include, but are not limited to:

In other embodiments, the presently disclosed cationic polymers comprise a specific poly(amido amine alcohol) structure having disulfide linking groups in the polymer backbone and an independent non-reducible amine contacting group at the terminal ends of the polymer.

In yet other embodiments, the presently disclosed cationic polymer comprises a copolymer of representative oligomers as described hereinabove. Such embodiments include, but are not limited to, a poly(amido amine) structure having disulfides in the polymer backbone and an independently degradable (non-reducible) group at at least one end of the polymer. Such embodiments also include using a cross-linker to add bioreducible linkages to hydrolytically degradable materials and also provide for higher molecular weight materials. A representative example of this embodiment, along with suitable monomers is as follows:

In particular embodiments, the presently disclosed polymer is selected from the group consisting of:

Further aspects of the presently disclosed subject matter include: (a) the R substituent groups that make up the presently disclosed polymers degrade via different biodegradation mechanisms within the same polymer. These biodegradation mechanisms can include hydrolytic, bioreducible, enzymatic, and/or other modes of degradation; (b) the ends of the polymer include a minority structure that differs from the majority structure that comprises most of the polymer backbone; (c) in several embodiments, the side chain molecules contain hydroxyl (OH)/alcohol groups. In some embodiments: (a) the backbone is bioreducible and the end groups of the polymer degrade hydrolytically; (b) the backbone degrades hydrolytically and the end groups are bioreducible; and (c) hydrolytically degradable oligomers are cross-linked with a bioreducible cross-linker; (d) bioreducible oligomers form block copolymers with hydrolytically degradable oligomers; and (e) the end group/minority structure comprises an amino acid or chain of amino acids, whereas the backbone degrades hydrolytically and/or is bioreducible.

One way to synthesize the presently disclosed materials is by the conjugate addition of amine-containing molecules to acrylates or acrylamides. This reaction can be done neat or in a solvent, such as DMSO or THF. Reactions can take place at a temperature ranging from about room temperature up to about 90° C. and can have a duration from about a few hours to about a few weeks. The presently disclosed methods can be used to create linear or branched polymers. In some embodiments, the molecular weight (MW) has a range from about 1 kDa to about 5 kDa, in other embodiments, the MW has a range from about 5 kDa to about 10 kDa, in other embodiments the MW has a range from about 10 kDa to about 15 kDa, in other embodiments, the MW has a range from about 15 kDa to about 25 kDa, in other embodiments, the MW has a range from about 25 kDa to about 50 kDa, and in other embodiments, the MW has a range from about 50 kDa to about 100 kDa. In other embodiments, the polymer forms a network, gel, and/or scaffold of apparent molecular weight greater than 100 kDa.

In particular embodiments, the presently disclosed subject matter provides hydrolytic and bioreducible polymeric particle formulations for the delivery of one or more peptides to a target. In some embodiments of the presently disclosed formulations, the particles are nanoparticles and, in other embodiments, they are microparticles. Some applications are to cancer and others are to ophthalmic diseases.

Accordingly, in some embodiments, the presently disclosed approach includes degradable nanoparticles, microparticles, and gels that release a peptide, which is capable of therapeutic activity through multiple modes of action. The presently disclosed peptides can simultaneously inhibit: (1) endothelial cell proliferation; (2) endothelial cell adhesion, (3) endothelial cell migration, (4) tumor cell proliferation, (5) tumor cell adhesion, and (6) tumor cell migration.

When combined with such peptides, the presently disclosed nanoparticles, microparticles, and gels: (1) protect and increase the persistence of the peptides that would otherwise be rapidly cleared in vivo; (2) allow passive targeting of tumor vasculature via nanoparticle biophysical properties to enable enhanced efficacy at the target site of action; (3) enable extended peptide release and minimized dosing schedules for affected patients; and (4) facilitate a continuous peptide concentration rather than a pulsatile profile that would be caused by bolus injections and fast clearance.

The presently disclosed microparticles have similar benefits to the nanoparticles except that they also persist longer and have an easier route for clinical administration. On the other hand, another advantage of the presently disclosed nanoparticles is that they are better able to passively target the peptides to tumor vasculature than are the microparticles. Representative embodiments of the presently disclosed microparticles are provided in Example 10, herein below.

Further, in some embodiments, one or more peptides, which can be the same or different, can be combined, e.g., encapsulated, directly or individually into different nanoparticles that then can be combined into the same microparticles.

C. Biodegradable Nanoparticles for Sustained Peptide Delivery

Selected polymers are able to encapsulate selected peptides possessing varied chemical properties. Changes to polymer structure, including small changes to the ends of the polymer only, can vary biophysical properties of these particles. These properties can be important to tune for effective in vivo peptide delivery. A small subset of the potential polymer library was screened to measure the effect of encapsulating the antiangiogenic peptides chemokinostatin-1 and pentastatin-1 within polymeric particles compared to unencapsulated, free peptides. Polymeric encapsulation of peptides enhanced the ability of the peptides to inhibit the proliferation of endothelial cells. An example of representative polymers encapsulating peptides is provided in Scheme 5.

Scheme 5 Representative polymer B3-S3-E6 synthesized at a B:S molar ratio of a 1.05:1 at 90° C. and representative encapsulated peptides.

Theor. Namae Sequence pI MW DEAH box poly8 (“DEAH” disclosed as EIELVEEEPPF (SEQ ID NO: 2485)  3.51 1330.45 SEQ ID NO: 2484) Wispostatin-1 SPWSPCSTSCGLGVSTRI (SEQ ID NO: 2360)  7.80 1838.08 Pentastatin LRRFSTMPFMFCNINNVCNF (SEQ ID NO: 2375)  9.02 2454.93 Chemokinostatin NGRKACLNPASPIVKKIIEKMLNS (SEQ ID NO: 2388) 10.03 2625.19

In other embodiments, particles synthesized and composed as described above are then used as a “core” inner particle for future coatings to create multi-component (also referred to herein as multi-layer) particles. For other embodiments, other nanoparticles are used as cores, such as an inorganic nanoparticles (like gold) or soft polymeric nanoparticles, for example, as disclosed in International PCT Patent Application Publication No. WO/2010/132879 for “Multicomponent Degradable Cationic Polymers,” to Green et al., which is incorporated herein by reference in its entirety. In each embodiment, the core particle is then coated with charged polymers as described above, peptides as described above, and other biological agents. Exemplary embodiments of multilayer particles are illustrated in FIG. 1.

Layering can be mediated by electrostatic forces and alternate cationic and anionic layers can be used to incorporate additional peptides and biological agents. Polyelectrolytes, including degradable polymers and peptides, also are used to provide structure to the multilayers. Multilayers can release drugs, peptides, and biological agents from the particle due to hydrolytic degradation, enzyme activity, disulfide reduction, and/or diffusion.

D. Polymeric Gels for Controlled Release of Biological Agents.

i. Hydrogels (or “Organogels”) for Protein/Peptide Release

In some embodiments, the presently disclosed subject matter provides photocrosslinked gels for controlled release of cargo, including, but not limited to peptides and proteins. Such gels can be tuned for release of other drugs. In some embodiments, for example, as illustrated in FIG. 2, a solution of acrylate-terminated polymers is made using either acrylate-terminated polymers, such as poly(β-amino esters) (PBAEs), poly(ethylene glycol) diacrylate (PEGDA), small crosslinkers including, but not limited to, 1,4-butanediol diacrylate, or a mixture of the above. Because many of these materials are amphiphilic, a variety of solvents can be used, including water, PBS, and DMSO, to encapsulate drugs within them. Addition of a small amount (0.05% w/v) of photoinitiator and exposure to long-wave UV light for a period of time, e.g., 5-15 min at 1-3 mW, causes formation of a drug-loaded gel.

The gel swelling properties can vary with pH by taking advantage of the PBAE portions, which can be reversibly protonated. Changing ratios of PBAE to PEGDA and the addition of crosslinkers changes swelling properties by changing pore size or overall hydrophobicity. For example, doping in increasing amounts of a more hydrophobic PBAE (B4S4) into a network of hydrophilic PEGDA causes the release kinetics to slow when measuring protein release.

E. Stable Formulations

To increase stability of nanoparticles in suspension, especially with hydrolytically-degradable polymers, the presently disclosed subject matter provides a method of keeping DNA or other cargo stable and functional after storage. For example, freeze-drying often causes denaturation of biological molecules or irreversible aggregation and inactivation of nanoparticles. Referring now to FIG. 3, by adding sucrose as a lyoprotectant at a final concentration of, for example, 7.5-45 mg/mL, the presently disclosed subject matter demonstrates that particles can be freeze dried and stored, for example, at 4° C. or −20° C. for extended periods, e.g., months, without significant change in physicochemical or biological properties. Certain formulations, when stored dry, also might be stable at ambient temperatures up to 40° C. Furthermore, the presently disclosed process allows particles to be prepared in advance and used much more easily in a clinical setting. The presently disclosed subject matter also demonstrates that particles can be concentrated in this way much more highly than would be possible with free polymer, which may be advantageous for dose adjustment in clinical or pre-clinical models.

F. Inclusion of Lyophilized Nanoparticles into Pellets/Scaffolds for Long-Term Delivery

The presently disclosed nanoparticles can be stored in a dry form and can be used in gene delivery via three-dimensional (3D) constructs. While DNA is used as a cargo in this example, other cargos of interest to one skilled in the art including, but not limited to, siRNA, peptides, protein, imaging agents, and the like, can be used, as well. In other embodiments, DNA-loaded nanoparticles were incorporated into natural and synthetic scaffolds, disks, microparticles, and hydrogels for various potential applications.

G. Methods of Treating Angiogenesis-Dependent Diseases

Although significant progress has been made in treating angiogenesis-dependent diseases, such as cancers, major challenges remain in terms of development of drug resistance, metastasis and overall survival rates. Studies designed to decipher the modes of drug resistance have revealed that tumors are very versatile and use multiple pathways to continue to survive and metastasize. See Chiang A C, Massague J. Molecular basis of metastasis. N Engl J Med 2008; 359(26):2814-23; Gupta G P, Massague J. Cancer metastasis: building a framework. Cell 2006; 127(4):679-95. Resistance has been observed for both cytotoxic and antiangiogenic agents. Thus, multimodal therapeutic design emerges as a promising, and perhaps even a mandatory strategy for treatment of cancer. See Sawyers C L. Cancer: mixing cocktails. Nature 2007; 449(7165):993-6; Dorrell M I, Aguilar E, Scheppke L, Barnett F H, Friedlander M. Combination angiostatic therapy completely inhibits ocular and tumor angiogenesis. Proc Natl Acad Sci USA 2007; 104(3):967-72.

The key attributes of tumor growth and metastasis are: angiogenesis, which facilitates the supply of the growing tumor with oxygen and nutrients; lymphangiogenesis, which facilitates the spreading of cancer cells through the lymphatics; and cancer cell proliferation. Angiogenesis, in particular, plays a critical role in the growth of tumors and antiangiogenic therapies have the potential to treat cancer, either alone or in combination with conventional chemotherapies, by starving tumors of oxygen and nutrients. There is a need, however, to find more potent anti-cancer therapeutics, including antiangiogenic therapeutics, as well as delivery systems for these therapeutics. The presently disclosed subject matter can address all of these attributes in a combined system.

Many forms of cancer, including breast cancer, are dependent on angiogenesis, the growth of blood vessels. There is a great medical need for the development of a safe, effective, and inexpensive means of antiangiogenic therapy. One promising approach is the use of antiangiogenic peptides as the active agents. In some embodiments, the presently disclosed subject matter provides peptides derived from several classes of proteins that are effective at preventing angiogenesis. In other embodiments, the presently disclosed subject matter provides other peptides that are able to inhibit cancer through additional mechanisms including, but not limited to, antilymphangiogenesis and apoptosis. In their current form, however, all of these peptides have a short in vivo half-life and they are not suitable for systemic administration or for long-term action. Thus, there is a need to package, protect, and deliver these peptides in a more stable, sustained fashion.

Accordingly, the presently disclosed biomaterials facilitate delivery of combinations of these peptides in an engineered fashion to synergistically kill cancer or treat other diseases, in particular, other angiogenesis-dependent diseases. More particularly, the presently disclosed subject matter provides an effective array of safe, biodegradable polymers for use in forming peptide-containing nanoparticles, microparticles, gels, and conjugates. The presently disclosed biomaterials can be used to construct particles, gels, and conjugates that vary in their biophysical properties and in biological properties, such as tumor accumulation and peptide release.

The presently disclosed formulations work through one or more of the following mechanisms: antiangiogenesis; inhibition of human endothelial cell proliferation and migration; inhibition of lymphatic endothelial cell proliferation and migration; and promotion of cancer apoptosis, as well as other mechanisms. The presently disclosed materials and methods can safely, effectively, and relatively inexpensively treat age-related macular degeneration (AMD), cancer, and other diseases.

Further, siRNA is a promising technology to silence the activity of many biological targets in many diseases including cancer, cardiovascular diseases, infectious diseases, neurological diseases, ophthalmic diseases, and others. In some cases, siRNA can be used to reach previously undruggable targets. The method of delivery and examples described herein for siRNA delivery apply equally to other similar RNA molecules including, but not limited to isRNA, agRNA, saRNA, and miRNA.

H. Nanoparticle-Mediated Multimodal Peptide Delivery

Conventional anti-angiogenesis treatments have proven to be very expensive with limited clinical success, particularly in breast cancer. The presently disclosed strategy combines more effective and multimodal therapeutic agents with nanomedicine to provide a delivery system to enhance their therapeutic effect. More particularly, the presently disclosed subject matter provides a single system that incorporates multimodal therapeutic activity, including, but not limited to, antiangiogenic activity, antilymphangiogenic activity, and apoptotic activity, and can be effective in limiting both tumor growth and metastasis.

Generally, small peptides possess many advantageous characteristics as therapeutic agents, including high specificity and low toxicity. Reichert J. Development trends for peptide therapeutics. Tufts Center for the Study of Drug Development 2008 [cited 2010]. [cited 2010. The main disadvantage of small peptides as therapeutic agents, however, is their short half-life. The presently disclosed subject matter capitalizes on the advantages of peptide agents by developing novel antiangiogenic, antilymphangiogenic, and apoptotic peptides targeting multiple pathways, and overcoming the disadvantages by designing a multi-agent nanocarrier system.

Approximately 25 peptides have been approved by the FDA, however, to date none of these approved peptides are antiangiogenic. Rosca E V, Koskimaki J E, Rivera C G, Pandey N B, Tamiz A P, Popel A S. Anti-angiogenic peptides for cancer therapeutics. Curr Pharm Biotechnol, 12(8):1101-1116 (2011). Several endogenous proteins/polypeptides, including angiostatin, endostatin, proteolytic fragments of collagen IV, pigment epithelium-derived factor, and thrombospondin, have antiangiogenic properties and can induce apoptosis in endothelial cells. Lucas R, Holmgren L, Garcia I, Jimenez B, Mandriota S J, Borlat F, et al. Multiple forms of angiostatin induce apoptosis in endothelial cells. Blood 1998; 92(12):4730-41. These proteins/polypeptides are large, however, and are not ideal for use as therapeutic agents. Further, full length human proteins, although theoretically not foreign to an individual's body, induce an immune response in some individuals.

More recently, a bioinformatics approach has allowed identification of candidate antiangiogenic regions of several proteins and synthetic peptides corresponding to those short sequences that possess the ability to suppress proliferation and migration of vascular endothelial cells in vitro and angiogenesis in vivo. Delivering such peptides to a cell and prolonging the duration of their activity, however, remains a challenge.

Although peptides are much easier to produce and are more scalable and less immunogenic than full-length proteins, they are eliminated from the body more quickly. The presently disclosed subject matter can increase and sustain residence time, increase accumulation in tumor vasculature, and maximize the therapeutic effects of such peptides. The presently disclosed subject matter combines biomaterial synthesis, sustained drug delivery, and anti-cancer peptide creation to provide nanoparticle-, microparticle-, and gel-based systems for sustained peptide delivery. The presently disclosed biodegradable biomaterials can be tuned for the encapsulation, protection, and sustained release of each type of peptide.

The use of the presently disclosed nanoparticles, microparticles, and gels limits toxicity because they can extravasate from the leaky neovasculature of the tumors and be trapped in the interstitium of the tumor once the anti-angiogenic compounds kill or normalize the vasculature. Further, the presently disclosed subject matter demonstrates that effective biomaterials for anti-cancer peptide nanoparticles, microparticles, and gels can be fabricated. Multiple anti-cancer peptides and other peptides can be combined within the same particle for multimodal peptide delivery, as well as multimodal therapy with other active agents including, but not limited to, other peptides, nucleic acids, proteins, small molecules, and the like.

More particularly, in some embodiments, the presently disclosed subject matter provides peptides that work through multiple biological mechanisms in combination with the presently disclosed biomaterials, including multilayer and multi-peptide nanoparticle formulations. An array of biodegradable polymers can be used to encapsulate peptides to create nanoparticles having varied biophysical properties and release kinetics. Each peptide can have a specialized subset of materials employed for its encapsulation. Referring now to FIG. 4, differing chemical structures can be synthesized by the conjugate addition of amines to acrylates or acrylamides of differing structure. The polymer structure can be tuned through variation to the backbone, side chain, end-group, hydrophobicity, and degradability. Unlike the polymeric materials disclosed in International PCT Patent Application Publication No. WO/2010/132879 for “Multicomponent Degradable Cationic Polymers,” to Green et al., which are cationic, i.e., positively charged, the presently disclosed polymers can be positively charged, whereas others can be negatively charged, others neutral and hydrophobic, and still others amphiphilic. The diversity of the presently disclosed biomaterials comes from the chemical diversity of the R groups (R, R′, R″) in the biomaterial array and from parameter tuning during particle fabrication.

For example, to create the presently disclosed multi-peptide particles, hydrophobic core particles first are constructed by self-assembly, for example between the somatotropin-derived peptide, the collagen IV-derived peptide, and a hydrophobic polymer. These nanoparticles are then coated by charged biodegradable polymers and peptides following a particle coating and layer-by-layer technique that modifies techniques previously described. Green J J, Chiu E, Leshchiner E S, Shi J, Langer R, Anderson D G. Electrostatic ligand coatings of nanoparticles enable ligand-specific gene delivery to human primary cells. Nano Lett 2007; 7(4):874-9; Shmueli R B, Anderson D G, Green J J. Electrostatic surface modifications to improve gene delivery. Expert Opin Drug Deliv 7(4):535-50. Through this process, the charged peptides (serpin-derived and chemokine-derived) can be incorporated into these multilayers. Charged biological agents, such as peptides and nucleic acids, can serve as both the therapeutic agent and the support polyelectrolyte in the presently disclosed systems.

In one embodiment, peptides can self-assemble with the presently disclosed polymers in an aqueous buffer due to physical, hydrophobic, and electrostatic forces. Zhang S, Uludag H. Nanoparticulate systems for growth factor delivery. Pharm Res 2009; 26(7):1561-80. In other embodiments, peptide-containing micelles can be formed by synthetic polymer-mPEG (e.g., E15 from FIG. 4) block copolymers. Depending on formulation parameters, polymer/peptide particle sizes can be tuned from approximately 50 nm to approximately 500 nm.

As an alternative strategy for polymers in the library that are more hydrophobic or have higher glass transition temperatures, peptides can be encapsulated by a double emulsion procedure. In this method, droplets of aqueous buffer containing peptide are dispersed in the hydrophobic polymer phase and then the polymer phase is itself dispersed in another aqueous phase to form the polymeric particles. Jain R A. The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices. Biomaterials 2000; 21(23):2475-90. As an alternative technique, blends of novel hydrophobic polymers and poly(lactic-co-glycolic acid) also can be made to form particles with unique degradation properties. Little S R, Lynn D M, Ge Q, Anderson D G, Puram S V, Chen J Z, et al. Poly-beta amino ester-containing microparticles enhance the activity of nonviral genetic vaccines. Proc Natl Acad Sci USA 2004; 101(26):9534-9.

I. Peptides for Anti-Angiogenesis, Anti-Lymphangiogenesis, Anti-Tumor, and Anti-Permeability Activity.

Several classes of peptides have been developed that show either anti-proliferative or anti-migratory activity or both on endothelial cells. These peptides appear to function through distinct mechanisms of action and have been tested both in vitro and in vivo in tumor xenografts and in ocular mouse models. These peptides include a 24-mer peptide NGRKACLNPASPIVKKIIEKMLNS (SEQ ID NO: 2388) derived from the CXC chemokine protein GRO-a/CXCL1 and a collagen IV derived and modified 20-mer peptideLRRFSTMPFMF-Abu-NINNV-Abu-NF (SEQ ID NO: 2452) as a highly potent anti-proliferative and anti-migratory peptide targeting avo1 integrins on both endothelial and tumor cells; here Abu is the 2-Aminobutyric acid introduced in the sequence to facilitate translation to human.

An 11-mer anti-angiogenic peptide EIELVEEEPPF (SEQ ID NO: 2485) derived from the serpin domain of DEAH box polypeptide (“DEAH” disclosed as SEQ ID NO: 2484) also has been identified that shows significant inhibition of MDA-MB-231 tumor xenograft growth. A somatotropin family peptide LLRISLLLIESWLE (SEQ ID NO: 2483; SP5033) derived from transmembrane45 proteinthat also has been identified and has anti-proliferative and anti-migratory activity on both endothelial cells and lymphatic endothelial cells. It is believed that this peptide is the first antilymphangiogenic peptide agent. Combining these peptides together can result in a peptide-based system that inhibits angiogenesis by several different mechanisms and also inhibits lymphangiogenesis that has been shown to promote tumor metastasis.

Representative peptides suitable for encapsulation with the presently disclosed biomaterials include those disclosed in International PCT Patent Application Publication Number WO2007/033215 A2 for “Compositions Having Antiangiogenic Activity and Uses Thereof,” to Popel et al., published Mar. 22, 2007; International PCT Patent Application Publication Number WO2008/085828 A2 for “Peptide Modulators of Angiogenesis and Use Thereof,” to Popel, published Jul. 17, 2008; U.S. Provisional Patent Application No. 61/421,706, filed Dec. 12, 2010, which is commonly owned; and U.S. Provisional Patent Application No. 61/489,500, filed May 24, 2011, which also is commonly owned, each of which is incorporated herein by reference in its entirety.

Accordingly, in some embodiments, peptide suitable for use in the presently disclosed subject matter are disclosed in Tables 1-10 of International PCT Patent Application Publication Number WO2008/085828 A2 for “Peptide Modulators of Angiogenesis and Use Thereof,” to Popel, published Jul. 17, 2008, which is incorporated herein by reference in its entirety.

Accordingly, in some embodiments, the presently disclosed subject matter provides a nanoparticle, microparticle, or gel comprising one or more peptides, wherein the one or more peptide is selected from the group consisting of an isolated peptide or analog thereof comprising one of the following amino acid sequences:

TSP Motif: (SEQ ID NO: 2486) W-X(2)-C-X(3)-C-X(2)-G , CXC Motif: G-X(3)-C-L Collagen Motif: (SEQ ID NO: 2487) C-N-X(3)-V-C Collagen Motif: P-F-X(2)-C Somatotropin Motif: (SEQ ID NO: 2488) L-X(3)-L-L-X(3)-S-X-L Serpin Motif: (SEQ ID NO: 2489) L-X(2)-E-E-X-P

wherein X denotes a variable amino acid and the number in parentheses denotes the number of variable amino acids; W denotes tryptophan; C denotes cysteine, G denotes glycine, V denotes valine; L denotes leucine, P is proline, and wherein the peptide reduces blood vessel formation in a cell, tissue or organ.

In other embodiments, the one or more peptide comprises an amino acid sequence shown in Table 1-6, 8 and 9.

In other embodiments, the one or more peptide comprises an isolated peptide or analog thereof having at least 85% identity to an amino acid sequence shown in Table 1-10.

In other embodiments, the one or more peptide comprises an amino acid sequence shown in Table 1-10. In yet other embodiments, the one or more peptide consists essentially of an amino acid sequence shown in Table 1-10.

In particular embodiments, the one or more peptide comprises an isolated peptide or analog thereof comprising or consisting essentially of a sequence having at least 85% amino acid sequence identity to an amino acid sequence selected from the group consisting of:

Placental Lactogen (SEQ ID NO: 2483) LLRISLLLIESWLE hGH-V (SEQ ID NO: 2490) LLRISLLLTQSWLE GH2 (SEQ ID NO: 2491) LLHISLLLIQSWLE Chorionic somatomammotropin (SEQ ID NO: 2480) LLRLLLLIESWLE Chorionic somatomammotropin hormone-like 1 (SEQ ID NO: 2482) LLHISLLLIESRLE Transmembrane protein 45A (SEQ ID NO: 2481) LLRSSLILLQGSWF IL-17 receptor C (SEQ ID NO: 2477) RLRLLTLQSWLL Neuropeptide FF receptor 2 (SEQ ID NO: 2479) LLIVALLFILSWL Brush border myosin-I (SEQ ID NO: 2478) LMRKSQILISSWF wherein the peptide reduces blood vessel formation in a cell, tissue or organ.

In yet more particular embodiments, the one or more peptide comprises an isolated peptide or analog thereof comprising or consisting essentially of a sequence having at least 85% amino acid sequence identity to an amino acid sequence selected from the group consisting of:

DEAH box polypeptide 8 (SEQ ID NO: 2485) (″DEAH″ disclosed as SEQ ID EIELVEEEPPF NO: 2484) Caspase 10 (SEQ ID NO: 2492) AEDLLSEEDPF CKIP-1 (SEQ ID NO: 2493) TLDLIQEEDPS wherein the peptide reduces blood vessel formation in a cell, tissue or organ.

In further embodiments, the one or more peptide comprises an isolated peptide or analog thereof comprising or consisting essentially of a sequence having at least 85% amino acid sequence identity to an amino acid sequence selected from the group consisting of:

Collagen type IV, alpha6 fibril (SEQ ID NO: 2494) LPRFSTMPFIYCNINEVCHY wherein the peptide reduces blood vessel formation in a cell, tissue or organ.

TABLE 1 The TSP-1 containing 20-mer with all the possible amino acid substitutions (SEQ ID NO: 2495) AA#1 AA#2 AA#3 AA#4 AA#5 AA#6 AA#7 AA#8 AA#9 AA#10 S (9) P (13) W (29) S (14) P (9) C (29) S (26) V (7) T (15) C (29) T (9) E (5) T (5) A (5) N (2) A (6) S (10) G (6) S (3) G (5) Q (4) T (1) R (5) R (3) Q (2) A (2) E (2) D (3) K (4) N (1) A (1) Q (1) D (1) E (3) G (2) K (1) R (1) K (1) S (2) A (1) R (1) T (2) V (1) E (1) AA#11 AA#12 AA#13 AA#14 AA#15 AA#16 AA#17 AA#18 AA#19 AA#20 G (26) G (10) G (29) V (8) Q (11) T (10) R (26) S (5) R (15) R (1) S (2) K (4) I (4) S (7) F (4) S (2) T (5) V (1) N (1) R (4) M (3) R (6) K (3) Q (1) V (5) M (4) T (3) K (2) Q (3) R (3) T (2) H (2) Y (2) S (3) H (3) L (2) A (1) A (1) L (2) E (2) D (1) E (1) E (1) Q (2) S (1) F (1) M (1) A (1) P (1) K (1) N (1) I (1) R (1) V (1) S (1) Q (1) W (1) Y (1)

TABLE 2 TSPs Motif: W-X(2)-C-X(3)-C-X(2)-G (SEQ ID NO: 2486) Number of Locations: 166 Number of Different Proteins: 54 SEQ Accession Number| First Last ID NO: Protein Name Aminoacid Aminoacid Sequence 1 O00622|CYR61_HUMAN 236 246 WsqCsktCgtG 2 O14514|BAI1_HUMAN 270 280 WgeCtrdCggG 3 O14514|BAI1_HUMAN 363 373 WsvCsstCgeG 4 O14514|BAI1_HUMAN 418 428 WslCsstCgrG 5 O14514|BAI1_HUMAN 476 486 WsaCsasCsqG 6 O14514|BAI1_HUMAN 531 541 WgsCsvtCgaG 7 O15072|ATS3_HUMAN 975 985 WseCsvtCgeG 8 O60241|BAI2_HUMAN 306 316 WsvCsltCgqG 9 O60241|BAI2_HUMAN 361 371 WslCsrsCgrG 10 O60241|BAI2_HUMAN 416 426 WgpCstsCanG 11 O60241|BAI2_HUMAN 472 482 WslCsktCdtG 12 O60242|BAI3_HUMAN 300 310 WstCsvtCgqG 13 O60242|BAI3_HUMAN 354 364 WslCsftCgrG 14 O60242|BAI3_HUMAN 409 419 WsqCsvtCsnG 15 O60242|BAI3_HUMAN 464 474 WsgCsksCdgG 16 O75173|ATS4_HUMAN 529 539 WgdCsrtCggG 17 O76076|WISP2_HUMAN 201 211 WgpCsttCglG 18 O95185|UNC50_HUMAN 269 279 WsvCnsrCgrG 19 O95388|WISP1_HUMAN 223 233 WspCstsCglG 20 O95389|WISP3_HUMAN 216 226 WtpCsrtCgmG 21 O95450|ATS2_HUMAN 863 873 WspCskpCggG 22 O95450|ATS2_HUMAN 984 994 WsqCsvtCgnG 23 P07996|TSP1_HUMAN 388 398 WtsCstsCgnG 24 P07996|TSP1_HUMAN 444 454 WssCsvtCgdG 25 P07996|TSP1_HUMAN 501 511 WdiCsvtCggG 26 P13671|CO6_HUMAN 32 42 WtsCsktCnsG 27 P13671|CO6_HUMAN 75 85 WqrCpinCllG 28 P14222|PERF_HUMAN 374 384 WrdCsrpCppG 29 P27918|PROP_HUMAN 86 96 WapCsvtCseG 30 P27918|PROP_HUMAN 145 155 WepCsvtCskG 31 P27918|PROP_HUMAN 202 212 WtpCsasChgG 32 P29279|CTGF_HUMAN 206 216 WsaCsktCgmG 33 P35442|TSP2_HUMAN 390 400 WtqCsvtCgsG 34 P35442|TSP2_HUMAN 446 456 WssCsvtCgvG 35 P35442|TSP2_HUMAN 503 513 WsaCtvtCagG 36 P48745|NOV_HUMAN 213 223 WtaCsksCgmG 37 P49327|FAS_HUMAN 627 637 WeeCkgrCppG 38 P58397|ATS12_HUMAN 551 561 WshCsrtCgaG 39 P58397|ATS12_HUMAN 832 842 WteCsvtCgtG 40 P58397|ATS12_HUMAN 952 962 WseCsysCggG 41 P58397|ATS12_HUMAN 1321 1331 WseCsttCglG 42 P58397|ATS12_HUMAN 1372 1382 WskCsrnCsgG 43 P58397|ATS12_HUMAN 1431 1441 WsqCsrsCggG 44 P58397|ATS12_HUMAN 1479 1489 WdlCstsCggG 45 P59510|ATS20_HUMAN 976 986 WsqCsrsCggG 46 P59510|ATS20_HUMAN 1031 1041 WseClvtCgkG 47 P59510|ATS20_HUMAN 1086 1096 WgpCtttCghG 48 P59510|ATS20_HUMAN 1162 1172 WtpCsysCgrG 49 P59510|ATS20_HUMAN 1217 1227 WspCsasCghG 50 P59510|ATS20_HUMAN 1314 1324 WgsCsssCsgG 51 P59510|ATS20_HUMAN 1368 1378 WgeCsqtCggG 52 P59510|ATS20_HUMAN 1427 1437 WtsCsasCgkG 53 P59510|ATS20_HUMAN 1483 1493 WneCsvtCgsG 54 P59510|ATS20_HUMAN 1664 1674 WskCsvtCgiG 55 P82987|ATL3_HUMAN 84 94 WsdCsrtCggG 56 P82987|ATL3_HUMAN 427 437 WtaCsysCggG 57 P82987|ATL3_HUMAN 487 497 WsqCtvtCgrG 58 P82987|ATL3_HUMAN 573 583 WsaCsttCgpG 59 P82987|ATL3_HUMAN 712 722 WgpCsatCgvG 60 P82987|ATL3_HUMAN 768 778 WqqCsrtCggG 61 P82987|ATL3_HUMAN 828 838 WskCsysCgvG 62 P82987|ATL3_HUMAN 1492 1502 WsqCsysCgeG 63 P82987|ATL3_HUMAN 1606 1616 WkpCtaaCgrG 64 Q13591|SEM5A_HUMAN 604 614 WspCsttCgiG 65 Q13591|SEM5A_HUMAN 662 672 WerCtaqCggG 66 Q13591|SEM5A_HUMAN 793 803 WsqCsrdCsrG 67 Q13591|SEM5A_HUMAN 850 860 WtkCsatCggG 68 Q496M8|CI094_HUMAN 259 269 WsaCtrsCggG 69 Q6S8J7|POTE8_HUMAN 27 37 WecCcfpCcrG 70 Q6UXZ4|UNC5D_HUMAN 261 271 WsaCnvrCgrG 71 Q6UY14|ATL4_HUMAN 53 63 WasCsqpCgvG 72 Q6UY14|ATL4_HUMAN 732 742 WtsCsrsCgpG 73 Q6UY14|ATL4_HUMAN 792 802 WsqCsvrCgrG 74 Q6UY14|ATL4_HUMAN 919 929 WgeCsseCgsG 75 Q6UY14|ATL4_HUMAN 979 989 WspCsrsCqgG 76 Q6ZMM2|ATL5_HUMAN 44 54 WtrCsssCgrG 77 Q76LX8|ATS13_HUMAN 1081 1091 WmeCsysCgdG 78 Q86TH1|ATL2_HUMAN 56 66 WtaCsrsCggG 79 Q86TH1|ATL2_HUMAN 631 641 WseCsrtCgeG 80 Q86TH1|ATL2_HUMAN 746 756 WgpCsgsCgqG 81 Q86TH1|ATL2_HUMAN 803 813 WerCnttCgrG 82 Q86TH1|ATL2_HUMAN 862 872 WseCtktCgvG 83 Q8IUL8|CILP2_HUMAN 155 165 WgpCsgsCgpG 84 Q8IZJ1|UNC5B_HUMAN 255 265 WspCsnrCgrG 85 Q8N6G6|ATL1_HUMAN 42 52 WseCsrtCggG 86 Q8N6G6|ATL1_HUMAN 385 395 WtaCsssCggG 87 Q8N6G6|ATL1_HUMAN 445 455 WspCtvtCgqG 88 Q8TE56|ATS17_HUMAN 552 562 WsmCsrtCgtG 89 Q8TE56|ATS17_HUMAN 809 819 WegCsvqCggG 90 Q8TE56|ATS17_HUMAN 870 880 WspCsatCekG 91 Q8TE56|ATS17_HUMAN 930 940 WsqCsasCgkG 92 Q8TE56|ATS17_HUMAN 981 991 WstCsstCgkG 93 Q8TE57|ATS16_HUMAN 595 605 WspCsrtCggG 94 Q8TE57|ATS16_HUMAN 936 946 WsaCsrtCggG 95 Q8TE57|ATS16_HUMAN 995 1005 WaeCshtCgkG 96 Q8TE57|ATS16_HUMAN 1060 1070 WsqCsvtCerG 97 Q8TE57|ATS16_HUMAN 1135 1145 WsqCtasCggG 98 Q8TE58|ATS15_HUMAN 848 858 WgpCsasCgsG 99 Q8TE58|ATS15_HUMAN 902 912 WspCsksCgrG 100 Q8TE59|ATS19_HUMAN 642 652 WspCsrtCsaG 101 Q8TE59|ATS19_HUMAN 924 934 WedCdatCggG 102 Q8TE59|ATS19_HUMAN 985 995 WtpCsrtCgkG 103 Q8TE59|ATS19_HUMAN 1096 1106 WskCsitCgkG 104 Q8TE60|ATS18_HUMAN 598 608 WseCsrtCggG 105 Q8TE60|ATS18_HUMAN 940 950 WstCskaCagG 106 Q8TE60|ATS18_HUMAN 1000 1010 WsqCsktCgrG 107 Q8TE60|ATS18_HUMAN 1061 1071 WseCsatCglG 108 Q8TE60|ATS18_HUMAN 1132 1142 WqqCtvtCggG 109 Q8WNS8|ATS14_HUMAN 856 866 WapCskaCggG 110 Q8WNS8|ATS14_HUMAN 977 987 WsqCsatCgeG 111 Q92947|GCDH_HUMAN 225 235 WarCedgCirG 112 Q96RW7|HMCN1_HUMAN 4538 4548 WraCsvtCgkG 113 Q96RW7|HMCN1_HUMAN 4595 4605 WeeCtrsCgrG 114 Q96RW7|HMCN1_HUMAN 4652 4662 WgtCsesCgkG 115 Q96RW7|HMCN1_HUMAN 4709 4719 WsaCsysCggG 116 Q96RW7|HMCN1_HUMAN 4766 4776 WgtCsrtCngG 117 Q96RW7|HMCN1_HUMAN 4823 4833 WsqCsasCggG 118 Q99732|LITAF_HUMAN 116 126 WlsCgslCllG 119 Q90014|THS7B_HUMAN 49 59 WgrCtgdCgpG 120 Q90014|THS7B_HUMAN 345 355 WspCsktCrsG 121 Q90014|THS7B_HUMAN 746 756 WtpCprmCgaG 122 Q90014|THS7B_HUMAN 1009 1019 WgsCsssCgiG 123 Q90014|THS7B_HUMAN 1258 1268 WteCsqtCghG 124 Q90014|THS7B_HUMAN 1381 1391 WstCeltCidG 125 Q9H324|ATS10_HUMAN 530 540 WgdCsrtCggG 126 Q9H324|ATS10_HUMAN 808 818 WtkCsagCagG 127 Q9H324|ATS10_HUMAN 867 877 WslCsrsCdaG 128 Q9H324|ATS10_HUMAN 927 937 WseCtpsCgpG 129 Q9H324|ATS10_HUMAN 986 996 WgeCsaqCgvG 130 Q9HCB6|SPON1_HUMAN 510 520 WspCsisCgmG 131 Q9HCB6|SPON1_HUMAN 567 577 WdeCsatCgmG 132 Q9HCB6|SPON1_HUMAN 623 633 WsdCsvtCgkG 133 Q9HCB6|SPON1_HUMAN 677 687 WseCnksCgkG 134 Q9HCB6|SPON1_HUMAN 763 773 WseCtklCggG 135 Q9NS62|THSD1_HUMAN 349 359 WsqCsatCgdG 136 Q9P283|SEM5B_HUMAN 615 625 WalCstsCgiG 137 Q9P283|SEM5B_HUMAN 673 683 WskCssnCggG 138 Q9P283|SEM5B_HUMAN 804 814 WssCsrdCelG 139 Q9P283|SEM5B_HUMAN 861 871 WspCsasCggG 140 Q9P2N4|ATS9_HUMAN 1006 1016 WteCsksCdgG 141 Q9P2N4|ATS9_HUMAN 1061 1071 WseClvtCgkG 142 Q9P2N4|ATS9_HUMAN 1116 1126 WvqCsvtCgqG 143 Q9P2N4|ATS9_HUMAN 1191 1201 WtpCsatCgkG 144 Q9P2N4|ATS9_HUMAN 1247 1257 WssCsvtCgqG 145 Q9P2N4|ATS9_HUMAN 1337 1347 WgaCsstCagG 146 Q9P2N4|ATS9_HUMAN 1391 1401 WgeCtklCggG 147 Q9P2N4|ATS9_HUMAN 1450 1460 WssCsysCgrG 148 Q9P2N4|ATS9_HUMAN 1506 1516 WsqCsysCgrG 149 Q9P2N4|ATS9_HUMAN 1564 1574 WqeCtktCgeG 150 Q9P2N4|ATS9_HUMAN 1621 1631 WseCsvtCgkG 151 Q9P2N4|ATS9_HUMAN 1686 1696 WgsCsysCgvG 152 Q9UH18|ATS1_HUMAN 568 578 WgdCsrtCggG 153 Q9UH18|ATS1_HUMAN 863 873 WgeCsksCelG 154 Q9UH18|ATS1_HUMAN 917 927 WssCsktCgkG 155 Q9UKP4|ATS7_HUMAN 547 557 WsiCsrsCgmG 156 Q9UKP4|ATS7_HUMAN 924 934 WtkCtvtCgrG 157 Q9UKP5|ATS6_HUMAN 519 529 WgeCsrtCggG 158 Q9UKP5|ATS6_HUMAN 801 811 WseCsatCagG 159 Q9UNA0|ATS5_HUMAN 576 586 WgqCsrsCggG 160 Q9UNA0|ATS5_HUMAN 884 894 WlaCsrtCdtG 161 Q9UP79|ATS8_HUMAN 536 546 WgeCsrtCggG 162 Q9UP79|ATS8_HUMAN 842 852 WseCsstCgaG 163 Q9UPZ6|THS7A_HUMAN 203 213 WseCsktCgsG 164 Q9UPZ6|THS7A_HUMAN 780 790 WtsCpssCkeG 165 Q9UPZ6|THS7A_HUMAN 1044 1054 WsrCsksCgsG 166 Q9UPZ6|THS7A_HUMAN 1423 1433 WslCqltCvnG

TABLE 3 The C-X-C chemokine 22-mer with all the possible amino acid substitutions (SEQ ID NO: 2496) AA#1 AA#2 AA#3 AA#4 AA#5 AA#6 AA#7 AA#8 AA#9 AA#10 AA#11 N (4) G (6) R (3) K (3) A (2) C (6) L (6) D (4) P (6) A (2) A (3) D (2) K (3) E (2) I (2) N (2) E (2) S (2) Q (1) L (1) D (1) E (1) V (1) K (1) AA#12 AA#13 AA#14 AA#15 AA#16 AA#17 AA#18 AA#19 AA#20 AA#21 AA#22 P (6) F (2) V (3) K (4) K (5) I (3) I (4) E (3) K (6) I (3) L (6) I (1) L (2) Q (2) R (1) V (3) V (2) Q (3) F (1) M (1) I (1) K (1) R (1) M (1) W (1)

TABLE 4 CXCs Motif: G-X(3)-C-L Number of Locations: 1337 Number of Different Proteins: 1170 SEQ ID Accession Number| First Last  NO: Protein Name Amino acid Amino acid Sequence 167 O00142|KITM_HUMAN 62 67 GkttCL 168 O00167|EYA2_HUMAN 361 366 GanlCL 169 O00220|TR10A_HUMAN 332 337 GeagCL 170 O00291|HIP1_HUMAN 699 704 GattCL 171 O00409|FOXN3_HUMAN 465 470 GirsCL 172 O00444|PLK4_HUMAN 775 780 GhriCL 173 O00462|MANBA_HUMAN 744 749 GeavCL 174 O00468|AGRIN_HUMAN 1549 1554 GdhpCL 175 O00468|AGRIN_HUMAN 2012 2017 GfvgCL 176 O00476|NPT4_HUMAN 144 149 GcvcCL 177 O00488|ZN593_HUMAN 41 46 GlhrCL 178 O00501|CLD5_HUMAN 10 15 GlvlCL 179 O00624|NPT3_HUMAN 220 225 GcvcCL 180 O14514|BAI1_HUMAN 243 248 GpenCL 181 O14522|PTPRT_HUMAN 736 741 GtplCL 182 O14548|COX7R_HUMAN 97 102 GtiyCL 183 O14617|AP3D1_HUMAN 1113 1118 GhhvCL 184 O14628|ZN195_HUMAN 51 56 GlitCL 185 O14772|FPGT_HUMAN 515 520 GnktCL 186 O14773|TPP1_HUMAN 2 7 GlqaCL 187 O14792|OST1_HUMAN 261 266 GrdrCL 188 O14817|TSN4_HUMAN 68 73 GfvgCL 189 O14841|OPLA_HUMAN 1240 1245 GdvfCL 190 O14842|FFAR1_HUMAN 166 171 GspvCL 191 O14894|T4S5_HUMAN 100 105 GaiyCL 192 O14981|BTAF1_HUMAN 608 613 GawlCL 193 O15021|MAST4_HUMAN 1534 1539 GsheCL 194 O15031|PLX62_HUMAN 308 313 GaglCL 195 O15056|SYNJ2_HUMAN 27 32 GrddCL 196 O15060|ZBT39_HUMAN 272 277 GtnsCL 197 O15063|K0355_HUMAN 244 249 GcdgCL 198 O15067|PUR4_HUMAN 914 919 GlvtCL 199 O15067|PUR4_HUMAN 1040 1045 GpsyCL 200 O15084|ANR28_HUMAN 449 454 GnleCL 201 O15084|ANR28_HUMAN 549 554 GhrlCL 202 O15084|ANR28_HUMAN 661 666 GhseCL 203 O15105|SMAD7_HUMAN 293 298 GngfCL 204 O15146|MUSK_HUMAN 648 653 GkpmCL 205 O15229|KMO_HUMAN 320 325 GfedCL 206 O15230|LAMA5_HUMAN 1933 1938 GrtqCL 207 O15296|LX15B_HUMAN 157 162 GwphCL 208 O15305|PMM2_HUMAN 5 10 GpalCL 209 O15354|GPR37_HUMAN 448 453 GcyfCL 210 O15379|HDAC3_HUMAN 214 219 GryyCL 211 O15397|IPO8_HUMAN 148 153 GsllCL 212 O15554|KCNN4_HUMAN 263 268 GkivCL 213 O43156|K0406_HUMAN 642 647 GkdfCL 214 O43175|SERA_HUMAN 111 116 GmimCL 215 O43175|SERA_HUMAN 416 421 GfgeCL 216 O43184|ADA12_HUMAN 407 412 GmgvCL 217 O43283|M3K13_HUMAN 133 138 GlfgCL 218 O43396|TXNLI_HUMAN 32 37 GcgpCL 219 O43396|TXNLI_HUMAN 144 149 GfdnCL 220 O43405|COCH_HUMAN 10 15 GlgvCL 221 O43541|SMAD6_HUMAN 363 368 GsgfCL 222 O43609|SPY1_HUMAN 219 224 GtcmCL 223 O43638|FREA_HUMAN 315 320 GltpCL 224 O43747|AP1G1_HUMAN 65 70 GgleCL 225 O43820|HYAL3_HUMAN 12 17 GvalCL 226 O43837|IDH3B_HUMAN 181 186 GvieCL 227 O43889|CREB3_HUMAN 330 335 GntsCL 228 O60244|CRSP2_HUMAN 447 452 GnseCL 229 O60266|ADCY3_HUMAN 44 49 GsclCL 230 O60266|ADCY3_HUMAN 944 949 GgieCL 231 O60292|SI1L3_HUMAN 658 663 GekvCL 232 O60423|AT8B3_HUMAN 238 243 GdvvCL 233 O60504|VINEX_HUMAN 478 483 GehiCL 234 O60508|PRP17_HUMAN 320 325 GerrCL 235 O60613|SEP15_HUMAN 4 9 GpsgCL 236 O60656|UD19_HUMAN 510 515 GyrkCL 237 O60662|KBTBA_HUMAN 447 452 GmiyCL 238 O60669|MOT2_HUMAN 93 98 GllcCL 239 O60673|DPOLZ_HUMAN 47 52 GqktCL 240 O60704|TPST2_HUMAN 229 234 GkekCL 241 O60706|ABCC9_HUMAN 1046 1051 GitlCL 242 O60883|ETBR2_HUMAN 315 320 GcyfCL 243 O75037|KI21B_HUMAN 1454 1459 GpvmCL 244 O75037|KI21B_HUMAN 1617 1622 GltpCL 245 O75052|CAPON_HUMAN 420 425 GrrdCL 246 O75077|ADA23_HUMAN 487 492 GggaCL 247 O75078|ADA11_HUMAN 429 434 GggsCL 248 O75094|SLIT3_HUMAN 1428 1433 GepyCL 249 O75095|MEGF6_HUMAN 695 700 GaclCL 250 O75173|ATS4_HUMAN 19 24 GagpCL 251 O75173|ATS4_HUMAN 419 424 GyghCL 252 O75311|GLRA3_HUMAN 387 392 GmgpCL 253 O75326|SEM7A_HUMAN 499 504 GchgCL 254 O75342|LX12B_HUMAN 299 304 GegtCL 255 O75342|LX12B_HUMAN 552 557 GfprCL 256 O75346|ZN253_HUMAN 131 136 GlnqCL 257 O75426|FBX24_HUMAN 119 124 GrrrCL 258 O75436|VP26A_HUMAN 169 174 GiedCL 259 O75443|TECTA_HUMAN 1687 1692 GdgyCL 260 O75445|USH2A_HUMAN 1668 1673 GfvgCL 261 O75445|USH2A_HUMAN 4401 4406 GqglCL 262 O75446|SAP30_HUMAN 64 69 GqlcCL 263 O75508|CLD11_HUMAN 164 169 GavlCL 264 O75569|PRKRA_HUMAN 268 273 GqyqCL 265 O75592|MYCB2_HUMAN 1087 1092 GfgvCL 266 O75636|FCN3_HUMAN 16 21 GgpaCL 267 O75678|RFPL2_HUMAN 117 122 GcavCL 268 O75679|RFPL3_HUMAN 56 61 GctvCL 269 O75689|CENA1_HUMAN 37 42 GvfiCL 270 O75691|UTP20_HUMAN 2132 2137 GalgCL 271 O75694|NU155_HUMAN 230 235 GkdgCL 272 O75843|AP1G2_HUMAN 67 72 GqmeCL 273 O75886|STAM2_HUMAN 42 47 GakdCL 274 O75911|DHRS3_HUMAN 168 173 GhivCL 275 O75916|RGS9_HUMAN 642 647 GsgtCL 276 O75923|DYSF_HUMAN 378 383 GahfCL 277 O75923|DYSF_HUMAN 1574 1579 GpqeCL 278 O75925|PIAS1_HUMAN 431 436 GvdgCL 279 O75954|TSN9_HUMAN 4 9 GcicCL 280 O75954|TSN9_HUMAN 68 73 GflgCL 281 O76000|OR2B3_HUMAN 108 113 GateCL 282 O76013|K1H6_HUMAN 58 63 GlgsCL 283 O76064|RNF8_HUMAN 15 20 GrswCL 284 O76075|DFFB_HUMAN 43 48 GsrlCL 285 O94759|TRPM2_HUMAN 272 277 GnltCL 286 O94759|TRPM2_HUMAN 713 718 GkttCL 287 O94761|RECQ4_HUMAN 543 548 GlppCL 288 O94779|CNTN5_HUMAN 169 174 GhygCL 289 O94779|CNTN5_HUMAN 265 270 GsyiCL 290 O94779|CNTN5_HUMAN 454 459 GmyqCL 291 O94829|IPO13_HUMAN 159 164 GqgrCL 292 O94856|NFASC_HUMAN 312 317 GeyfCL 293 O94887|FARP2_HUMAN 192 197 GqqhCL 294 O94900|TOX_HUMAN 22 27 GpspCL 295 O94907|DKK1_HUMAN 107 112 GvqiCL 296 O94919|ENDD1_HUMAN 371 376 GiesCL 297 O94933|SLIK3_HUMAN 898 903 GfvdCL 298 O94955|RHBT3_HUMAN 386 391 GkinCL 299 O94956|SO2B1_HUMAN 449 454 GmllCL 300 O95071|EDD1_HUMAN 531 536 GtqvCL 301 O95153|RIMB1_HUMAN 79 84 GaeaCL 302 O95153|RIMB1_HUMAN 1485 1490 GlasCL 303 O95163|IKAP_HUMAN 472 477 GfkvCL 304 O95202|LETM1_HUMAN 43 48 GlrnCL 305 O95210|GET1_HUMAN 285 290 GdheCL 306 O95239|KIF4A_HUMAN 27 32 GcqmCL 307 O95248|MTMR5_HUMAN 159 164 GlnyCL 308 O95248|T1MR5_HUMAN 381 386 GyrwCL 309 O95255|MRP6_HUMAN 845 850 GalvCL 310 O95255|MRP6_HUMAN 943 948 GtplCL 311 O95255|MRP6_HUMAN 992 997 GllgCL 312 O95256|I18RA_HUMAN 447 452 GyslCL 313 O95279|KCNK5_HUMAN 122 127 GvplCL 314 O95294|RASL1_HUMAN 130 135 GqgrCL 315 O95342|ABCBB_HUMAN 327 332 GfvwCL 316 O95373|IPO7_HUMAN 147 152 GillCL 317 O95396|MOCS3_HUMAN 250 255 GvlgCL 318 O95405|ZFYV9_HUMAN 137 142 GnlaCL 319 O95477|ABCA1_HUMAN 2120 2125 GrfrCL 320 O95500|CLD14_HUMAN 178 183 GtllCL 321 O95551|TTRAP_HUMAN 217 222 GnelCL 322 O95602|RPA1_HUMAN 1556 1561 GitrCL 323 O95620|DUS4L_HUMAN 125 130 GygaCL 324 O95633|FSTL3_HUMAN 88 93 GlvhCL 325 O95671|ASML_HUMAN 588 593 GeyqCL 326 O95714|HERC2_HUMAN 717 722 GsthCL 327 O95714|HERC2_HUMAN 3265 3270 GalhCL 328 O95714|HERC2_HUMAN 4047 4052 GgkhCL 329 O95715|SCYBE_HUMAN 68 73 GgehCL 330 O95780|ZN682_HUMAN 132 137 GlnqCL 331 O95803|NDST3_HUMAN 815 820 GktkCL 332 O95858|TSN15_HUMAN 285 290 GtgcCL 333 O95873|CF047_HUMAN 171 176 GpeeCL 334 O95886|DLGP3_HUMAN 284 289 GgpfCL 335 O95967|FBLN4_HUMAN 76 81 GgylCL 336 O95977|EDG6_HUMAN 333 338 GpgdCL 337 O96006|ZBED1_HUMAN 221 226 GapnCL 338 O96008|TOM40_HUMAN 72 77 GacgCL 339 O96009|NAPSA_HUMAN 350 355 GvrlCL 340 P00505|AATM_HUMAN 268 273 GinvCL 341 P00750|TPA_HUMAN 515 520 GplyCL 342 P00751|CFAB_HUMAN 288 293 GakkCL 343 P01130|LDLR_HUMAN 314 319 GtneCL 344 P01133|EGF_HUMAN 741 746 GadpCL 345 P01266|THYG_HUMAN 2020 2025 GevtCL 346 P01375|TNFA_HUMAN 26 31 GsrrCL 347 P01730|CD4_HUMAN 366 371 GmwqCL 348 P01833|PIGR_HUMAN 437 442 GfywCL 349 P02775|SCYB7_HUMAN 101 106 GrkiCL 350 P02776|PLF4_HUMAN 37 42 GdlgCL 351 P02776|PLF4_HUMAN 79 84 GrkiCL 352 P02778|SCYBA_HUMAN 70 75 GekrCL 353 P02787|TRFE_HUMAN 209 214 GafkCL 354 P02787|TRFE_HUMAN 538 543 GafrCL 355 P02788|TRFL_HUMAN 213 218 GafkCL 356 P02788|TRFL_HUMAN 549 554 GafrCL 357 P03986|TCC_HUMAN 28 33 GtylCL 358 P04350|TBB4_HUMAN 235 240 GyttCL 359 P04920|B3A2_HUMAN 751 756 GvvfCL 360 P05108|CP11A_HUMAN 458 463 GvrqCL 361 P05141|ADT2_HUMAN 155 160 GlgdCL 362 P05549|AP2A_HUMAN 371 376 GiqsCL 363 P06401|PRGR_HUMAN 484 489 GasgCL 364 P06756|ITAV_HUMAN 905 910 GvagCL 365 P07202|PERT_HUMAN 819 824 GgfqCL 366 P07339|CATD_HUMAN 362 367 GktlCL 367 P07357|CO8A_HUMAN 117 122 GdqdCL 368 P07437|TBB5_HUMAN 235 240 GyttCL 369 P07686|HEXB_HUMAN 483 488 GgeaCL 370 P07814|SYEP_HUMAN 261 266 GhscCL 371 P07942|LAMB1_HUMAN 1052 1057 GqclCL 372 P07988|PSPB_HUMAN 244 249 GicgCL 373 P08151|GLI1_HUMAN 14 19 GepcCL 374 P08151|GLI1_HUMAN 828 833 GlapCL 375 P08243|ASNS_HUMAN 8 13 GsddCL 376 P08319|ADH4_HUMAN 241 246 GatdCL 377 P08582|TRFM_HUMAN 212 217 GafrCL 378 P08582|TRFM_HUMAN 558 563 GafrCL 379 P08686|CP21A_HUMAN 424 429 GaryCL 380 P08697|A2AP_HUMAN 139 144 GsgpCL 381 P08709|FA7_HUMAN 14 19 GlqgCL 382 P08922|ROS_HUMAN 2248 2253 GdviCL 383 P09001|RM03_HUMAN 291 296 GhknCL 384 P09326|CD48_HUMAN 5 10 GwdsCL 385 P09341|GROA_HUMAN 81 86 GrkaCL 386 P09848|LPH_HUMAN 1846 1851 GphaCL 387 P10071|GLI3_HUMAN 1359 1364 GpesCL 388 P10109|ADX_HUMAN 151 156 GcqiCL 389 P10145|IL8_HUMAN 73 78 GrelCL 390 P10635|CP2D6_HUMAN 439 444 GrraCL 391 P10646|TFPI1_HUMAN 213 218 GpswCL 392 P10720|PF4V_HUMAN 40 45 GdlgCL 393 P10720|PF4V_HUMAN 82 87 GrkiCL 394 P10745|IRBP_HUMAN 328 333 GvvhCL 395 P11047|LAMC1_HUMAN 903 908 GqceCL 396 P11362|FGFR1_HUMAN 337 342 GeytCL 397 P11717|MPRI_HUMAN 231 236 GtaaCL 398 P12236|ADT3_HUMAN 155 160 GlgdCL 399 P13473|LAMP2_HUMAN 228 233 GndtCL 400 P13498|CY24A_HUMAN 45 50 GvfvCL 401 P13569|CFTR_HUMAN 124 129 GiglCL 402 P13686|PPA5_HUMAN 215 220 GpthCL 403 P13804|ETFA_HUMAN 49 54 GevsCL 404 P13807|GYS1_HUMAN 185 190 GvglCL 405 P13861|KAP2_HUMAN 354 359 GdvkCL 406 P14222|PERF_HUMAN 530 535 GggtCL 407 P14543|NID1_HUMAN 24 29 GpvgCL 408 P14867|GBRA1_HUMAN 6 11 GlsdCL 409 P15151|PVR_HUMAN 119 124 GnytCL 410 P15538|C11B1_HUMAN 446 451 GmrqCL 411 P15692|VEGFA_HUMAN 168 173 GarcCL 412 P16109|LYAM3_HUMAN 271 276 GnmiCL 413 P16112|PGCA_HUMAN 2183 2188 GhviCL 414 P16581|LYAM2_HUMAN 376 381 GymnCL 415 P17038|ZNF43_HUMAN 127 132 GfnqCL 416 P17040|ZNF31_HUMAN 184 189 GnsvCL 417 P17936|IBP3_HUMAN 66 71 GcgcCL 418 P18510|IL1RA_HUMAN 87 92 GgkmCL 419 P18564|ITB6_HUMAN 674 679 GeneCL 420 P18577|RHCE_HUMAN 306 311 GgakCL 421 P19099|C11B2_HUMAN 446 451 GmrqCL 422 P19224|UD16_HUMAN 512 517 GyrkCL 423 P19367|HXK1_HUMAN 713 718 GdngCL 424 P19835|CEL_HUMAN 96 101 GdedCL 425 P19875|MIP2A_HUMAN 81 86 GqkaCL 426 P19876|MIP2B_HUMAN 81 86 GkkaCL 427 P19883|FST_HUMAN 252 257 GgkkCL 428 P20062|TCO2_HUMAN 79 84 GyqqCL 429 P20273|CD22_HUMAN 691 696 GlgsCL 430 P20648|ATP4A_HUMAN 108 113 GglgCL 431 P20701|ITAL_HUMAN 76 81 GtghCL 432 P20701|ITAL_HUMAN 1150 1155 GdpgCL 433 P20813|CP2B6_HUMAN 432 437 GkriCL 434 P20916|MAG_HUMAN 301 306 GvyaCL 435 P20929|NEBU_HUMAN 4517 4522 GvvhCL 436 P21554|CNR1_HUMAN 427 432 GdsdCL 437 P21580|TNAP3_HUMAN 99 104 GdgnCL 438 P21802|FGFR2_HUMAN 5 10 GrfiCL 439 P21802|FGFR2_HUMAN 338 343 GeytCL 440 P21817|RYR1_HUMAN 840 845 GpsrCL 441 P21860|ERBB3_HUMAN 513 518 GpggCL 442 P21964|COMT_HUMAN 30 35 GwglCL 443 P22064|LTB1S_HUMAN 938 943 GsfrCL 444 P22064|LTB1S_HUMAN 1359 1364 GsykCL 445 P22105|TENX_HUMAN 565 570 GrggCL 446 P22309|UD11_HUMAN 276 281 GginCL 447 P22309|UD11_HUMAN 513 518 GyrkCL 448 P22310|UD14_HUMAN 514 519 GyrkCL 449 P22314|UBE1_HUMAN 230 235 GvvtCL 450 P22455|FGFR4_HUMAN 97 102 GrylCL 451 P22455|FGFR4_HUMAN 220 225 GtytCL 452 P22455|FGFR4_HUMAN 329 334 GeytCL 453 P22607|FGFR3_HUMAN 335 340 GeytCL 454 P22680|CP7A1_HUMAN 330 335 GnpiCL 455 P22732|GTR5_HUMAN 348 353 GfsiCL 456 P23142|FBLN1_HUMAN 269 274 GihnCL 457 P23142|FBLN1_HUMAN 547 552 GgfrCL 458 P23416|GLRA2_HUMAN 376 381 GmghCL 459 P23759|PAX7_HUMAN 466 471 GgseCL 460 P24386|RAE1_HUMAN 395 400 GgiyCL 461 P24557|THAS_HUMAN 475 480 GprsCL 462 P24592|IBP6_HUMAN 100 105 GrgrCL 463 P24593|IBP5_HUMAN 96 101 GrgyCL 464 P24821|TENA_HUMAN 143 148 GagcCL 465 P24903|CP2F1_HUMAN 432 437 GrrlCL 466 P25205|MCM3_HUMAN 239 244 GtyrCL 467 P25874|UCP1_HUMAN 21 26 GiaaCL 468 P25940|CO5A3_HUMAN 1581 1586 GgetCL 469 P26374|RAE2_HUMAN 397 402 GgiyCL 470 P26951|IL3RA_HUMAN 363 368 GleeCL 471 P27487|DPP4_HUMAN 335 340 GrwnCL 472 P27540|ARNT_HUMAN 332 337 GskfCL 473 P27987|IP3KB_HUMAN 284 289 GtrsCL 474 P28332|ADH6_HUMAN 237 242 GateCL 475 P28340|DPOD1_HUMAN 709 714 GklpCL 476 P29274|AA2AR_HUMAN 162 167 GqvaCL 477 P29353|SHC1_HUMAN 570 575 GselCL 478 P29459|IL12A_HUMAN 33 38 GmfpCL 479 P30040|ERP29_HUMAN 153 158 GmpgCL 480 P30530|UFO_HUMAN 106 111 GqyqCL 481 P30532|ACHA5_HUMAN 279 284 GekiCL 482 P30566|PUR8_HUMAN 169 174 GkrcCL 483 P31323|KAP3_HUMAN 368 373 GtvkCL 484 P32004|L1CAM_HUMAN 308 313 GeyrCL 485 P32004|L1CAM_HUMAN 493 498 GryfCL 486 P32314|FOXN2_HUMAN 319 324 GirlCL 487 P32418|NAC1_HUMAN 414 419 GtygCL 488 P32929|CGL_HUMAN 80 85 GakyCL 489 P32970|TNFL7_HUMAN 29 34 GlviCL 490 P33402|GCYA2_HUMAN 284 289 GncsCL 491 P34913|HYES_HUMAN 258 263 GpavCL 492 P34981|TRFR_HUMAN 94 99 GyvgCL 493 P34998|CRFR1_HUMAN 83 88 GyreCL 494 P35227|PCGF2_HUMAN 316 321 GslnCL 495 P35251|RFC1_HUMAN 402 407 GaenCL 496 P35270|SPRE_HUMAN 6 11 GravCL 497 P35367|HRH1_HUMAN 96 101 GrplCL 498 P35452|HXD12_HUMAN 176 181 GvasCL 499 P35498|SCN1A_HUMAN 964 969 GqamCL 500 P35499|SCN4A_HUMAN 774 779 GqamCL 501 P35503|UD13_HUMAN 514 519 GyrkCL 502 P35504|UD15_HUMAN 514 519 GyrkCL 503 P35555|FBN1_HUMAN 1259 1264 GeyrCL 504 P35555|FBN1_HUMAN 1385 1390 GsyrCL 505 P35555|FBN1_HUMAN 1416 1421 GnggCL 506 P35555|FBN1_HUMAN 1870 1875 GsfyCL 507 P35555|FBN1_HUMAN 2034 2039 GsfkCL 508 P35556|FBN2_HUMAN 1303 1308 GeyrCL 509 P35556|FBN2_HUMAN 1952 1957 GsynCL 510 P35556|FBN2_HUMAN 1994 1999 GsfkCL 511 P35556|FBN2_HUMAN 2076 2081 GgfqCL 512 P35590|TIE1_HUMAN 280 285 GltfCL 513 P35916|VGFR3_HUMAN 4 9 GaalCL 514 P35968|VGFR2_HUMAN 638 643 GdyvCL 515 P36509|UD12_HUMAN 510 515 GyrkCL 516 P36888|FLT3_HUMAN 99 104 GnisCL 517 P37058|DHB3_HUMAN 13 18 GllvCL 518 P38398|BRCA1_HUMAN 949 954 GsrfCL 519 P38571|LICH_HUMAN 7 12 GlvvCL 520 P38571|LICH_HUMAN 58 63 GyilCL 521 P38606|VATA1_HUMAN 390 395 GrvkCL 522 P38607|VA1A2_HUMAN 388 393 GrvkCL 523 P39059|COFA1_HUMAN 8 13 GqcwCL 524 P40205|NCYM_HUMAN 100 105 GrppCL 525 P40939|ECHA_HUMAN 709 714 GfppCL 526 P41217|OX2G_HUMAN 117 122 GcymCL 527 P42331|RHG25_HUMAN 4 9 GqsaCL 528 P42345|FRAP_HUMAN 1479 1484 GrmrCL 529 P42785|PCP_HUMAN 339 344 GqvkCL 530 P42830|SCYB5_HUMAN 87 92 GkeiCL 531 P42892|ECE1_HUMAN 79 84 GlvaCL 532 P43378|PTN9_HUMAN 334 339 GdvpCL 533 P43403|ZAP70_HUMAN 113 118 GvfdCL 534 P43403|ZAP70_HUMAN 245 250 GliyCL 535 P46379|BAT3_HUMAN 872 877 GlfeCL 536 P46531|NOTC1_HUMAN 1354 1359 GslrCL 537 P47775|GPR12_HUMAN 166 171 GtsiCL 538 P47804|RGR_HUMAN 275 280 GiwgCL 539 P48048|IRK1_HUMAN 204 209 GgklCL 540 P48052|CBPA2_HUMAN 12 17 GhiyCL 541 P48059|PINC_HUMAN 176 181 GelyCL 542 P48067|SC6A9_HUMAN 457 462 GtqfCL 543 P48230|T4S4_HUMAN 5 10 GcarCL 544 P48745|NOV_HUMAN 60 65 GcscCL 545 P49247|RPIA_HUMAN 100 105 GgggCL 546 P49327|FAS_HUMAN 1455 1460 GlynCL 547 P49588|SYAC_HUMAN 897 902 GkitCL 548 P49640|EVX1_HUMAN 345 350 GpcsCL 549 P49641|MA2A2_HUMAN 862 867 GwrgCL 550 P49646|YYY1_HUMAN 393 398 GetpCL 551 P49753|ACOT2_HUMAN 296 301 GgelCL 552 P49903|SPS1_HUMAN 323 328 GlliCL 553 P49910|ZN165_HUMAN 32 37 GqdtCL 554 P50851|LRBA_HUMAN 2736 2741 GpenCL 555 P51151|RAB9A_HUMAN 79 84 GsdcCL 556 P51168|SCNNB_HUMAN 532 537 GsvlCL 557 P51589|CP2J2_HUMAN 444 449 GkraCL 558 P51606|RENBP_HUMAN 37 42 GfftCL 559 P51674|GPM6A_HUMAN 170 175 GanlCL 560 P51685|CCR8_HUMAN 150 155 GttlCL 561 P51790|CLCN3_HUMAN 520 525 GaaaCL 562 P51790|CLCN3_HUMAN 723 728 GlrgCL 563 P51793|CLCN4_HUMAN 520 525 GaaaCL 564 P51793|CLCN4_HUMAN 721 726 GlrgCL 565 P51795|CLCN5_HUMAN 506 511 GaaaCL 566 P51795|CLCN5_HUMAN 707 712 GlrgCL 567 P51800|CLCKA_HUMAN 613 618 GhqqCL 568 P51801|CLCKB_HUMAN 613 618 GhqqCL 569 P51957|NEK4_HUMAN 322 327 GegkCL 570 P52306|GDS1_HUMAN 25 30 GcldCL 571 P52306|GDS1_HUMAN 265 270 GlveCL 572 P52429|DGKE_HUMAN 411 416 GtkdCL 573 P52744|ZN138_HUMAN 48 53 GlnqCL 574 P52789|HXK2_HUMAN 713 718 GdngCL 575 P52803|EFNA5_HUMAN 147 152 GrrsCL 576 P52823|STC1_HUMAN 55 60 GafaCL 577 P52848|NDST1_HUMAN 824 829 GktkCL 578 P52849|NDST2_HUMAN 302 307 GkrlCL 579 P52849|NDST2_HUMAN 823 828 GktrCL 580 P52961|NAR1_HUMAN 220 225 GiwtCL 581 P53355|DAPK1_HUMAN 1326 1331 GkdwCL 582 P54132|BLM_HUMAN 891 896 GiiyCL 583 P54277|PMS1_HUMAN 837 842 GmanCL 584 P54750|PDE1A_HUMAN 32 37 GilrCL 585 P54753|EPHB3_HUMAN 297 302 GegpCL 586 P54826|GAS1_HUMAN 19 24 GawlCL 587 P55160|NCKPL_HUMAN 938 943 GpieCL 588 P55268|LAMB2_HUMAN 501 506 GcdrCL 589 P55268|LAMB2_HUMAN 1063 1068 GqcpCL 590 P56192|SYMC_HUMAN 8 13 GvpgCL 591 P56749|CLD12_HUMAN 63 68 GssdCL 592 P57077|TAK1L_HUMAN 68 73 GflkCL 593 P57679|EVC_HUMAN 683 688 GssqCL 594 P58215|LOXL3_HUMAN 13 18 GlllCL 595 P58397|ATS12_HUMAN 447 452 GwgfCL 596 P58418|USH3A_HUMAN 69 74 GscgCL 597 P58512|CU067_HUMAN 166 171 GfpaCL 598 P59047|NALP5_HUMAN 64 69 GlqwCL 599 P59510|ATS20_HUMAN 458 463 GygeCL 600 P60370|KR105_HUMAN 32 37 GtapCL 601 P60371|KR106_HUMAN 16 21 GsrvCL 602 P60409|KR107_HUMAN 16 21 GsrvCL 603 P60413|KR10C_HUMAN 11 16 GsrvCL 604 P60602|CT052_HUMAN 38 43 GtfsCL 605 P61011|SRP54_HUMAN 129 134 GwktCL 606 P61550|ENT1_HUMAN 343 348 GnasCL 607 P61619|S61A1_HUMAN 143 148 GagiCL 608 P62072|TIM10_HUMAN 46 51 GesvCL 609 P62312|LSM6_HUMAN 32 37 GvlaCL 610 P62714|PP2AB_HUMAN 161 166 GqifCL 611 P67775|PP2AA_HUMAN 161 166 GqifCL 612 P68371|TBB2C_HUMAN 235 240 GyttCL 613 P69849|NOMO3_HUMAN 507 512 GkvsCL 614 P78310|CXAR_HUMAN 219 224 GsdgCL 615 P78324|SHPS1_HUMAN 12 17 GpllCL 616 P78325|ADAM8_HUMAN 101 106 GqdhCL 617 P78346|RPP30_HUMAN 253 258 GdedCL 618 P78357|CNTP1_HUMAN 1205 1210 GfsgCL 619 P78423|X3CL1_HUMAN 350 355 GllfCL 620 P78504|JAG1_HUMAN 898 903 GprpCL 621 P78509|RELN_HUMAN 2862 2867 GhgdCL 622 P78524|ST5_HUMAN 127 132 GvaaCL 623 P78549|NTHL1_HUMAN 286 291 GqqtCL 624 P78559|MAP1A_HUMAN 2433 2438 GpqgCX 625 P80162|SCYB6_HUMAN 87 92 GkqvCL 626 P82279|CRUM1_HUMAN 1092 1097 GlqgCL 627 P83105|HTRA4_HUMAN 10 15 GlgrCL 628 P98088|MUC5A_HUMAN 853 858 GcprCL 629 P98095|FBLN2_HUMAN 1047 1052 GsfrCL 630 P98153|IDD_HUMAN 289 294 GddpCL 631 P98160|PGBM_HUMAN 3181 3186 GtyvCL 632 P98161|PKD1_HUMAN 649 654 GaniCL 633 P98164|LRP2_HUMAN 1252 1257 GhpdCL 634 P98164|LRP2_HUMAN 3819 3824 GsadCL 635 P98173|FAM3A_HUMAN 83 88 GpkiCL 636 P98194|AT2C1_HUMAN 158 163 GdtvCL 637 Q00872|MYPC1_HUMAN 447 452 GkeiCL 638 Q00973|B4GN1_HUMAN 408 413 GlgnCL 639 Q01064|PDE1B_HUMAN 243 248 GmvhCL 640 Q01433|AMPD2_HUMAN 103 108 GpapCL 641 Q02246|CNTN2_HUMAN 107 112 GvyqCL 642 Q02246|CNTN2_HUMAN 203 208 GnysCL 643 Q02318|CP27A_HUMAN 472 477 GvraCL 644 Q02985|FHR3_HUMAN 188 193 GsitCL 645 Q03923|ZNF85_HUMAN 133 138 GlnqCL 646 Q03923|ZNF85_HUMAN 184 189 GmisCL 647 Q03924|ZN117_HUMAN 103 108 GlnqCL 648 Q03936|ZNF92_HUMAN 132 137 GlnqCL 649 Q03938|ZNF90_HUMAN 132 137 GlnqCL 650 Q04721|NOTC2_HUMAN 476 481 GgftCL 651 Q05469|LIPS_HUMAN 716 721 GeriCL 652 Q06730|ZN33A_HUMAN 530 535 GktfCL 653 Q06732|ZN11B_HUMAN 531 536 GktfCL 654 Q07325|SCYB9_HUMAN 70 75 GvqtCL 655 Q07617|SPAG1_HUMAN 133 138 GsnsCL 656 Q07954|LRP1_HUMAN 875 880 GdndCL 657 Q07954|LRP1_HUMAN 3001 3006 GsykCL 658 Q08629|TICN1_HUMAN 178 183 GpcpCL 659 Q09428|ABCC8_HUMAN 1073 1078 GivlCL 660 Q10471|GALT2_HUMAN 535 540 GsnlCL 661 Q12796|PNRC1_HUMAN 63 68 GdgpCL 662 Q12805|FBLN3_HUMAN 66 71 GgylCL 663 Q12809|KCNH2_HUMAN 719 724 GfpeCL 664 Q12841|FSTL1_HUMAN 48 53 GeptCL 665 Q12852|M3K12_HUMAN 90 95 GlfgCL 666 Q12860|CNTN1_HUMAN 110 115 GiyyCL 667 Q12882|DPYD_HUMAN 988 993 GctlCL 668 Q12933|TRAF2_HUMAN 387 392 GykmCL 669 Q12986|NFX1_HUMAN 537 542 GdfsCL 670 Q13077|TRAF1_HUMAN 302 307 GyklCL 671 Q13129|RLF_HUMAN 48 53 GlrpCL 672 Q13200|PSMD2_HUMAN 135 140 GereCL 673 Q13224|NMDE2_HUMAN 584 589 GynrCL 674 Q13224|NMDE2_HUMAN 1392 1397 GddgCL 675 Q13255|MGR1_HUMAN 136 141 GinrCL 676 Q13275|SEM3F_HUMAN 305 310 GghcCL 677 Q13308|PTK7_HUMAN 429 434 GyldCL 678 Q13309|SKP2_HUMAN 107 112 GifsCL 679 Q13322|GRB10_HUMAN 219 224 GlerCL 680 Q13370|PDE3B_HUMAN 253 258 GgagCL 681 Q13371|PHLP_HUMAN 200 205 GcmiCL 682 Q13387|JIP2_HUMAN 594 599 GlfsCL 683 Q13410|BT1A1_HUMAN 8 13 GlprCL 684 Q13444|ADA15_HUMAN 405 410 GmgsCL 685 Q13470|TNK1_HUMAN 105 110 GglkCL 686 Q13485|SMAD4_HUMAN 359 364 GdrfCL 687 Q13554|KCC2B_HUMAN 472 477 GpppCL 688 Q13591|SEM5A_HUMAN 819 824 GgmpCL 689 Q13591|SEM5A_HUMAN 876 881 GgdiCL 690 Q13639|5HT4R_HUMAN 89 94 GevfCL 691 Q13642|FHL1_HUMAN 23 28 GhhcCL 692 Q13686|ALKB1_HUMAN 300 305 GlphCL 693 Q13698|CAC1S_HUMAN 1210 1215 GglyCL 694 Q13751|LAMB3_HUMAN 449 454 GrclCL 695 Q13772|NCOA4_HUMAN 97 102 GqfnCL 696 Q13772|NCOA4_HUMAN 364 369 GnlkCL 697 Q13795|ARFRP_HUMAN 159 164 GrrdCL 698 Q13822|ENPP2_HUMAN 21 26 GvniCL 699 Q13885|TBB2A_HUMAN 235 240 GyttCL 700 Q14008|CKAP5_HUMAN 109 114 GieiCL 701 Q14008|CKAP5_HUMAN 1237 1242 GvigCL 702 Q14114|LRP8_HUMAN 175 180 GnrsCL 703 Q14114|LRP8_HUMAN 336 341 GlneCL 704 Q14159|K0146_HUMAN 513 518 GtraCL 705 Q14264|ENR1_HUMAN 358 363 GeltCL 706 Q14315|FLNC_HUMAN 1649 1654 GlgaCL 707 Q14344|GNA13_HUMAN 314 319 GdphCL 708 Q14392|LRC32_HUMAN 360 365 GslpCL 709 Q14393|GAS6_HUMAN 138 143 GnffCL 710 Q14393|GAS6_HUMAN 217 222 GsysCL 711 Q14435|GALT3_HUMAN 93 98 GerpCL 712 Q14435|GALT3_HUMAN 513 518 GqplCL 713 Q14451|GRB7_HUMAN 517 522 GilpCL 714 Q14520|HABP2_HUMAN 121 126 GrggCL 715 Q14524|SCN5A_HUMAN 911 916 GqslCL 716 Q14566|MCM6_HUMAN 154 159 GtflCL 717 Q14593|ZN273_HUMAN 100 105 GlnqCL 718 Q14656|ITBA1_HUMAN 197 202 GvlsCL 719 Q14669|TRIPC_HUMAN 562 567 GladCL 720 Q14669|TRIPC_HUMAN 1136 1141 GgaeCL 721 Q14703|MBTP1_HUMAN 845 850 GdsnCL 722 Q14714|SSPN_HUMAN 91 96 GiivCL 723 Q14766|LTB1L_HUMAN 1139 1144 GsfrCL 724 Q14766|LTB1L_HUMAN 1560 1565 GsykCL 725 Q14767|LTBP2_HUMAN 990 995 GsytCL 726 Q14767|LTBP2_HUMAN 1156 1161 GsyqCL 727 Q14767|LTBP2_HUMAN 1197 1202 GsffCL 728 Q14767|LTBP2_HUMAN 1238 1243 GsfnCL 729 Q14767|LTBP2_HUMAN 1324 1329 GsfrCL 730 Q14767|LTBP2_HUMAN 1366 1371 GsflCL 731 Q14774|HLX1_HUMAN 483 488 GalgCL 732 Q14916|NPT1_HUMAN 110 115 GfalCL 733 Q14916|NPT1_HUMAN 207 212 GcavCL 734 Q14940|SL9A5_HUMAN 576 581 GsgaCL 735 Q14957|NMDE3_HUMAN 941 946 GpspCL 736 Q15021|CND1_HUMAN 730 735 GtigCL 737 Q15034|HERC3_HUMAN 145 150 GnwhCL 738 Q15048|LRC14_HUMAN 281 286 GrftCL 739 Q15058|KIF14_HUMAN 438 443 GfntCL 740 Q15061|WDR43_HUMAN 103 108 GtctCL 741 Q15147|PLCB4_HUMAN 987 992 GgsnCL 742 Q15155|NOMO1_HUMAN 507 512 GkvsCL 743 Q15274|NADC_HUMAN 92 97 GpahCL 744 Q15303|ERBB4_HUMAN 516 521 GpdgCL 745 Q15334|L2GL1_HUMAN 722 727 GvvrCL 746 Q15399|TLR1_HUMAN 663 668 GmqiCL 747 Q15413|RYR3_HUMAN 229 234 GhdeCL 748 Q15413|RYR3_HUMAN 1656 1661 GlrtCL 749 Q15418|KS6A1_HUMAN 548 553 GnpeCL 750 Q15546|PAQRB_HUMAN 185 190 GliyCL 751 Q15633|TRBP2_HUMAN 321 326 GlcgCL 752 Q15650|TRIP4_HUMAN 196 201 GsgpCL 753 Q15652|JHD2C_HUMAN 1864 1869 GfvvCL 754 Q15735|PI5PA_HUMAN 379 384 GpgrCL 755 Q15746|MYLK_HUMAN 229 234 GvytCL 756 Q15746|MYLK_HUMAN 579 584 GtytCL 757 Q15858|SCN9A_HUMAN 940 945 GqamCL 758 Q15911|ATBF1_HUMAN 3527 3532 GsyhCL 759 Q16342|PDCD2_HUMAN 121 126 GesvCL 760 Q16363|LAMA4_HUMAN 1001 1006 GfvgCL 761 Q16549|PCSK7_HUMAN 16 21 GlptCL 762 Q16617|NKG7_HUMAN 15 20 GlmfCL 763 Q16647|PTGIS_HUMAN 437 442 GhnhCL 764 Q16787|LAMA3_HUMAN 1526 1531 GvssCL 765 Q30KQ9|DB111_HUMAN 60 65 GthcCL 766 Q32MQ0|ZN750_HUMAN 121 126 GthrCL 767 Q3KNT7|NSN5B_HUMAN 134 139 GaehCL 768 Q3LI83|KR241_HUMAN 153 158 GqlnCL 769 Q3SYG4|PTHB1_HUMAN 822 827 GgrlCL 770 Q3T8J9|GON4L_HUMAN 1740 1745 GcadCL 771 Q495M9|USH1G_HUMAN 76 81 GhlhCL 772 Q496M8|CI094_HUMAN 170 175 GefsCL 773 Q499Z4|ZN672_HUMAN 40 45 GrfrCL 774 Q4G0F5|VP26B_HUMAN 167 172 GiedCL 775 Q4KMG0|CDON_HUMAN 93 98 GyyqCL 776 Q53G59|KLH12_HUMAN 426 431 GviyCL 777 Q53H47|SETMR_HUMAN 72 77 GtcsCL 778 Q53R12|T4S20_HUMAN 213 218 GflgCL 779 Q58EX2|SDK2_HUMAN 469 474 GtytCL 780 Q5HYK3|COQ5_HUMAN 240 245 GrflCL 781 Q5IJ48|CRUM2_HUMAN 243 248 GsfrCL 782 Q5JPE7|NOMO2_HUMAN 507 512 GkvsCL 783 Q5JQC9|AKAP4_HUMAN 242 247 GkskCL 784 Q5JVG8|ZN506_HUMAN 132 137 GlkqCL 785 Q5JWF2|GNAS1_HUMAN 2 7 GyrnCL 786 Q5JWF2|GNAS1_HUMAN 584 589 GtsgCL 787 Q5JWF8|CT134_HUMAN 111 116 GccyCL 788 Q5MJ68|SPDYC_HUMAN 138 143 GkdwCL 789 Q5NUL3|GP120_HUMAN 72 77 GataCL 790 Q5SRN2|CF010_HUMAN 117 122 GsikCL 791 Q5T2D3|OTUD3_HUMAN 72 77 GdgnCL 792 Q5T5C0|STXB5_HUMAN 322 327 GrrpCL 793 Q5T751|LCE1C_HUMAN 72 77 GggcCL 794 Q5T752|LCE1D_HUMAN 68 73 GggcCL 795 Q5T753|LCE1E_HUMAN 72 77 GggcCL 796 Q5T754|LCE1F_HUMAN 72 77 GggcCL 797 Q5T7P2|LCE1A_HUMAN 64 69 GggcCL 798 Q5T7P3|LCE1B_HUMAN 72 77 GggcCL 799 Q5TA78|LCE4A_HUMAN 55 60 GggcCL 800 Q5TA79|LCE2A_HUMAN 64 69 GggcCL 801 Q5TA82|LCE2D_HUMAN 68 73 GggcCL 802 Q5TCM9|LCE5A_HUMAN 64 69 GggcCL 803 Q5TEA3|CT194_HUMAN 465 470 GgngCL 804 Q5TEJ8|ICB1_HUMAN 39 44 GnecCL 805 Q5THJ4|VP13D_HUMAN 1215 1220 GslgCL 806 Q5VST9|OBSCN_HUMAN 3315 3320 GdryCL 807 Q5VST9|OBSCN_HUMAN 4189 4194 GvqwCL 808 Q5VST9|OBSCN_HUMAN 5195 5200 GvyrCL 809 Q5VST9|OBSCN_HUMAN 6425 6430 GvytCL 810 Q5VT25|MRCKA_HUMAN 1325 1330 GaltCL 811 Q5VUA4|ZN318_HUMAN 1984 1989 GpspCL 812 Q5VZ18|SHE_HUMAN 8 13 GasaCL 813 Q5VZM2|RRAGB_HUMAN 366 371 GpkgCL 814 Q5W111|CLLD6_HUMAN 50 55 GtggCL 815 Q5XUX1|FBXW9_HUMAN 184 189 GgslCL 816 Q5ZPR3|CD276_HUMAN 216 221 GtysCL 817 Q5ZPR3|CD276_HUMAN 434 439 GtysCL 818 Q5ZPR3|CD276_HUMAN 472 477 GlsvCL 819 Q63ZY6|NSN5C_HUMAN 216 221 GaehCL 820 Q63ZY6|NSN5C_HUMAN 293 298 GkgrCL 821 Q68CP9|ARID2_HUMAN 566 571 GfykCL 822 Q6BDS2|URFB1_HUMAN 549 554 GnlfCL 823 Q6GQQ9|OTU7B_HUMAN 190 195 GdgnCL 824 Q6GTX8|LAIR1_HUMAN 10 15 GlvlCL 825 Q6IS24|GLTL3_HUMAN 564 569 GtgrCL 826 Q6ISS4|LAIR2_HUMAN 10 15 GlvlCL 827 Q6ISS4|LAIR2_HUMAN 97 102 GlyrCL 828 Q6N022|TEN4_HUMAN 139 144 GrssCL 829 Q6NUM9|RETST_HUMAN 366 371 GnarCL 830 Q6P1M0|S27A4_HUMAN 297 302 GiggCL 831 Q6P1R4|DUS1L_HUMAN 209 214 GniqCL 832 Q6P587|FAHD1_HUMAN 96 101 GyalCL 833 Q6P656|CO026_HUMAN 144 149 GqdfCL 834 Q6PCB7|S27A1_HUMAN 300 305 GvggCL 835 Q6PCT2|FXL19_HUMAN 222 227 GgdaCL 836 Q6Q0C0|TRAF7_HUMAN 397 402 GpvwCL 837 Q6Q4G3|LAEVR_HUMAN 794 799 GledCL 838 Q6TGC4|PADI6_HUMAN 22 27 GteiCL 839 Q6UB99|ANR11_HUMAN 498 503 GssgCL 840 Q6UWJ8|C16L2_HUMAN 15 20 GgccCL 841 Q6UWN5|LYPD5_HUMAN 15 20 GaalCL 842 Q6UX01|LMBRL_HUMAN 394 399 GncyCL 843 Q6UX53|MET7B_HUMAN 199 204 GdgcCL 844 Q6UX65|TMM77_HUMAN 99 104 GilsCL 845 Q6UXV0|GFRAL_HUMAN 127 132 GmwsCL 846 Q6UY09|CEA20_HUMAN 226 231 GlyrCL 847 Q6V0L0|CP26C_HUMAN 455 460 GarsCL 848 Q6V0L0|CP26C_HUMAN 517 522 GnglCL 849 Q6VVB1|NHLC1_HUMAN 47 52 GhvyCL 850 Q6VVX0|CP2R1_HUMAN 444 449 GrrhCL 851 Q6W4X9|MUC6_HUMAN 1095 1100 GdceCL 852 Q6WN34|CRIDL2_HUMAN 54 59 GlmyCL 853 Q6ZN16|M3K15_HUMAN 82 87 GargCL 854 Q6ZN17|LN28B_HUMAN 103 108 GgspCL 855 Q6ZR16|CO039_HUMAN 141 146 GlstCL 856 Q6ZRQ5|CF167_HUMAN 1116 1121 GilkCL 857 Q6ZSY5|PPR3F_HUMAN 647 652 GaevCL 858 Q6ZV89|SH2D5_HUMAN 195 200 GghsCL 859 Q6ZVD8|PHLPL_HUMAN 5 10 GsrnCL 860 Q6ZW76|ANKS3_HUMAN 632 637 GqalCL 861 Q75N90|FBN3_HUMAN 551 556 GsfsCL 862 Q75N90|FBN3_HUMAN 1217 1222 GghrCL 863 Q75N90|FBN3_HUMAN 1826 1831 GsymCL 864 Q75N90|FBN3_HUMAN 1866 1871 GsynCL 865 Q75N90|FBN3_HUMAN 1908 1913 GsfhCL 866 Q75N90|FBN3_HUMAN 1990 1995 GsfqCL 867 Q7L099|RUFY3_HUMAN 37 42 GewlCL 868 Q7L0J3|SV2A_HUMAN 230 235 GrrqCL 869 Q7L3T8|SYPM_HUMAN 149 154 GkeyCL 870 Q7L622|K1333_HUMAN 310 315 GitdCL 871 Q7LBC6|JHD2B_HUMAN 1049 1054 GfgvCL 872 Q7LBC6|JHD2B_HUMAN 1388 1393 GrllCL 873 Q7RTN6|STRAD_HUMAN 294 299 GtvpCL 874 Q7RTP0|NIPA1_HUMAN 122 127 GklgCL 875 Q7RTU9|STRC_HUMAN 1077 1082 GacsCL 876 Q7RTX0|TS1R3_HUMAN 20 25 GaplCL 877 Q7Z2W7|TRPM8_HUMAN 652 657 GgsnCL 878 Q7Z333|SETX_HUMAN 1106 1111 GekkCL 879 Q7Z3K3|POGZ_HUMAN 749 754 GrqtCL 880 Q7Z3T1|OR2W3_HUMAN 108 113 GgveCL 881 Q7Z401|MYCPP_HUMAN 948 953 GsadCL 882 Q7Z460|CLAP1_HUMAN 146 151 GiclCL 883 Q7Z4S6|KI21A_HUMAN 1493 1498 GpvmCL 884 Q7Z5G4|GOGA7_HUMAN 68 73 GclaCL 885 Q7Z5K2|WAPL_HUMAN 850 855 GaerCL 886 Q7Z713|ANR37_HUMAN 75 80 GsleCL 887 Q7Z7E8|UB2Q1_HUMAN 36 41 GpgpCL 888 Q7Z7M0|MEGF8_HUMAN 403 408 GcgwCL 889 Q7Z7M1|GP144_HUMAN 343 348 GselCL 890 Q86SG6|NEK8_HUMAN 418 423 GsngCL 891 Q86SQ6|GP123_HUMAN 1058 1063 GraaCL 892 Q86SQ6|GP123_HUMAN 1091 1096 GhasCL 893 Q86T20|CF001_HUMAN 75 80 GvldCL 894 Q86T65|DAAM2_HUMAN 570 575 GappCL 895 Q86TX2|ACOT1_HUMAN 234 239 GgelCL 896 Q86U44|MTA70_HUMAN 479 484 GkehCL 897 Q86UE6|LRTM1_HUMAN 19 24 GvvlCL 898 Q86UK0|ABCAC_HUMAN 1251 1256 GwlcCL 899 Q86UK5|LBN_HUMAN 26 31 GgrgCL 900 Q86UQ4|ABCAD_HUMAN 4056 4061 GppfCL 901 Q86UQ4|ABCAD_HUMAN 4932 4937 GsfkCL 902 Q86UU1|PHLB1_HUMAN 119 124 GcmlCL 903 Q86UU1|PHLB1_HUMAN 1245 1250 GvdtCL 904 Q86UV5|UBP48_HUMAN 50 55 GnpnCL 905 Q86UW9|DTX2_HUMAN 347 352 GlpvCL 906 Q86V24|ADR2_HUMAN 190 195 GailCL 907 Q86V71|ZN429_HUMAN 132 137 GlnqCL 908 Q86VH4|LRTM4_HUMAN 271 276 GtfkCL 909 Q86WB7|UN93A_HUMAN 178 183 GasdCL 910 Q86WG5|MTMRD_HUMAN 369 374 GyrsCL 911 Q86WK7|AMGO3_HUMAN 348 353 GlfvCL 912 Q86WR7|CJ047_HUMAN 84 89 GgvcCL 913 Q86X76|NIT1_HUMAN 288 293 GpglCL 914 Q86XN8|RKHD1_HUMAN 192 197 GtdvCL 915 Q86Y01|DTX1_HUMAN 345 350 GlpvCL 916 Q86Y56|HEAT2_HUMAN 271 276 GwllCL 917 Q86YC3|LRC33_HUMAN 396 401 GlasCL 918 Q8IU80|TMPS6_HUMAN 503 508 GqpdCL 919 Q8IUK8|CBLN2_HUMAN 27 32 GcgsCL 920 Q8IUL8|CILP2_HUMAN 464 469 GcqkCL 921 Q8IVF6|ANR18_HUMAN 706 711 GykkCL 922 Q8IVH4|MMAA_HUMAN 96 101 GgraCL 923 Q8IWB7|WDFY1_HUMAN 200 205 GsvaCL 924 Q8IWN6|CX052_HUMAN 89 94 GskrCL 925 Q8IWV2|CNTN4_HUMAN 380 385 GmyqCL 926 Q8IWY4|SCUB1_HUMAN 342 347 GsfqCL 927 Q8IX30|SCUB3_HUMAN 337 342 GsfqCL 928 Q8IXI1|MIRO2_HUMAN 515 520 GqtpCL 929 Q8IXW0|CK035_HUMAN 268 273 GslpCL 930 Q8IY26|PPAC2_HUMAN 149 154 GtlyCL 931 Q8IY49|PAQRA_HUMAN 216 221 GvfyCL 932 Q8IYB9|ZN595_HUMAN 132 137 GvyqCL 933 Q8IYG6|LRC56_HUMAN 194 199 GnlvCL 934 Q8IZ96|CKLF1_HUMAN 112 117 GgslCL 935 Q8IZD0|SAM14_HUMAN 95 100 GgsfCL 936 Q8IZE3|PACE1_HUMAN 322 327 GetpCL 937 Q8IZF4|GP114_HUMAN 521 526 GkllCL 938 Q8IZJ1|UNC5B_HUMAN 547 552 GtfgCL 939 Q8IZL8|PELP1_HUMAN 317 322 GlarCL 940 Q8IZY2|ABCA7_HUMAN 2001 2006 GrfrCL 941 Q8N122|RPTOR_HUMAN 549 554 GgeaCL 942 Q8N122|RPTOR_HUMAN 1302 1307 GaisCL 943 Q8N1F7|NUP93_HUMAN 518 523 GdppCL 944 Q8N1G0|ZN687_HUMAN 1133 1138 GaggCL 945 Q8N283|ANR35_HUMAN 65 70 GlteCL 946 Q8N283|ANR35_HUMAN 703 708 GlwdCL 947 Q8N357|CB018_HUMAN 57 62 GefsCL 948 Q8N3C7|RSNL2_HUMAN 201 206 GavkCL 949 Q8N3V7|SYNPO_HUMAN 28 33 GsyrCL 950 Q8N441|FGRL1_HUMAN 334 339 GmyiCL 951 Q8N442|GUF1_HUMAN 334 339 GdtlCL 952 Q8N4B4|FBX39_HUMAN 114 119 GllsCL 953 Q8N5D0|WDTC1_HUMAN 48 53 GcvnCL 954 Q8N5D6|GBGT1_HUMAN 9 14 GlgfCL 955 Q8N655|CJ012_HUMAN 468 473 GdvkCL 956 Q8N6F8|WBS27_HUMAN 160 165 GglvCL 957 Q8N6T3|ARFG1_HUMAN 38 43 GiwiCL 958 Q8N6V9|TEX9_HUMAN 3 8 GrslCL 959 Q8N6Y1|PCD20_HUMAN 27 32 GpfsCL 960 Q8N6Y1|PCD20_HUMAN 881 886 GiyiCL 961 Q8N726|CD2A2_HUMAN 160 165 GrarCL 962 Q8N813|CC056_HUMAN 42 47 GsctCL 963 Q8N895|ZN366_HUMAN 695 700 GrdeCL 964 Q8N8A2|ANR44_HUMAN 543 548 GhrgCL 965 Q8N8A2|ANR44_HUMAN 645 650 GhtlCL 966 Q8N8Q9|NIPA2_HUMAN 112 117 GkigCL 967 Q8N8R3|MCATL_HUMAN 133 138 GsldCL 968 Q8N9B4|ANR42_HUMAN 142 147 GrlgCL 969 Q8N9B4|ANR42_HUMAN 281 286 GhieCL 970 Q8N9L9|ACOT4_HUMAN 234 239 GadiCL 971 Q8NB46|ANR52_HUMAN 434 439 GnveCL 972 Q8NB46|ANR52_HUMAN 732 737 GcedCL 973 Q8NB46|ANR52_HUMAN 802 807 GhedCL 974 Q8NB49|AT11C_HUMAN 110 115 GyedCL 975 Q8NBJ9|SIDT2_HUMAN 296 301 GmlfCL 976 Q8NBV4|PPAC3_HUMAN 128 133 GtilCL 977 Q8NCL4|GALT6_HUMAN 505 510 GtngCL 978 Q8NCL4|GALT6_HUMAN 593 598 GsgtCL 979 Q8NCN4|RN169_HUMAN 67 72 GcagCL 980 Q8NDX1|PSD4_HUMAN 183 188 GlkcCL 981 Q8NDX1|PSD4_HUMAN 821 826 GedhCL 982 Q8NEN9|PDZD8_HUMAN 724 729 GgliCL 983 Q8NFP4|MDGA1_HUMAN 622 627 GsaaCL 984 Q8NFP9|NBEA_HUMAN 2819 2824 GpenCL 985 Q8NFU7|CXXC6_HUMAN 1660 1665 GvtaCL 986 Q8NG94|O11H1_HUMAN 112 117 GtseCL 987 Q8NG99|OR7G2_HUMAN 109 114 GlenCL 988 Q8NGC9|O11H4_HUMAN 118 123 GtteCL 989 Q8NGH6|O52L2_HUMAN 96 101 GytvCL 990 Q8NGH7|O52L1_HUMAN 96 101 GyivCL 991 Q8NGI2|O52N4_HUMAN 95 100 GfdeCL 992 Q8NGJ0|OR5A1_HUMAN 111 116 GlseCL 993 Q8NGK5|O52M1_HUMAN 95 100 GldaCL 994 Q8NGR9|OR1N2_HUMAN 112 117 GldnCL 995 Q8NGS6|O13C3_HUMAN 108 113 GsteCL 996 Q8NGT2|O13J1_HUMAN 108 113 GsteCL 997 Q8NGT5|OR9A2_HUMAN 247 252 GygsCL 998 Q8NGT9|O2A42_HUMAN 107 112 GhseCL 999 Q8NGU2|OR9A4_HUMAN 251 256 GygsCL 1000 Q8NGZ9|O2T10_HUMAN 109 114 GaecCL 1001 Q8NH09|OR8S1_HUMAN 109 114 GteaCL 1002 Q8NH19|O10AG_HUMAN 99 104 GgteCL 1003 Q8NH40|OR6S1_HUMAN 66 71 GnlsCL 1004 Q8NHA8|OR1FC_HUMAN 50 55 GsdhCL 1005 Q8NHU2|CT026_HUMAN 158 163 GnipCL 1006 Q8NHU2|CT026_HUMAN 582 587 GfksCL 1007 Q8NHW6|OTOSP_HUMAN 8 13 GlalCL 1008 Q8NHX4|SPTA3_HUMAN 175 180 GsrsCL 1009 Q8NHY2|RFWD2_HUMAN 628 633 GkpyCL 1010 Q8NHY3|GA2L2_HUMAN 463 468 GpaeCL 1011 Q8TB24|RIN3_HUMAN 31 36 GmrlCL 1012 Q8TB24|RIN3_HUMAN 971 976 GsppCL 1013 Q8TCB7|METL6_HUMAN 89 94 GvgnCL 1014 Q8TCN5|ZN507_HUMAN 142 147 GmyrCL 1015 Q8TCT7|PSL1_HUMAN 262 267 GlysCL 1016 Q8TCT7|PSL1_HUMAN 329 334 GiafCL 1017 Q8TCT8|PSL2_HUMAN 321 326 GiafCL 1018 Q8TD26|CHD6_HUMAN 1627 1632 GnlcCL 1019 Q8TD43|TRPM4_HUMAN 238 243 GthgCL 1020 Q8TD43|TRPM4_HUMAN 306 311 GaadCL 1021 Q8TD43|TRPM4_HUMAN 650 655 GdatCL 1022 Q8TD43|TRPM4_HUMAN 764 769 GgrrCL 1023 Q8TDJ6|DMXL2_HUMAN 188 193 GkddCL 1024 Q8TDM6|DLG5_HUMAN 1672 1677 GvkdCL 1025 Q8TIDN|CABL1_HUMAN 135 140 GsgpCL 1026 Q8TDU6|GPBAR_HUMAN 81 86 GywsCL 1027 Q8TDU9|RL3R2_HUMAN 187 192 GvrlCL 1028 Q8TDV0|GP151_HUMAN 183 188 GvemCL 1029 Q8TDX9|PK1L1_HUMAN 317 322 GealCL 1030 Q8TDY2|RBCC1_HUMAN 897 902 GelvCL 1031 Q8TDZ2|MICA1_HUMAN 743 748 GhfyCL 1032 Q8TE49|OTU7A_HUMAN 206 211 GdgnCL 1033 Q8TE58|ATS15_HUMAN 418 423 GhgdCL 1034 Q8TE85|GRHL3_HUMAN 429 434 GvkgCL 1035 Q8TEM1|PO210_HUMAN 1489 1494 GdvlCL 1036 Q8TF62|AT8B4_HUMAN 282 287 GfliCL 1037 Q8TF76|HASP_HUMAN 190 195 GtsaCL 1038 Q8WTV0|SCRB1_HUMAN 319 324 GfcpCL 1039 Q8WUB8|PHF10_HUMAN 320 325 GhpsCL 1040 Q8WUM0|NU133_HUMAN 112 117 GgwaCL 1041 Q8WWQ8|STAB2_HUMAN 1358 1363 GngiCL 1042 Q8WWQ8|STAB2_HUMAN 2026 2031 GsggCL 1043 Q8WWN0|ASB5_HUMAN 179 184 GhheCL 1044 Q8WWZ1|IL1FA_HUMAN 63 68 GgsrCL 1045 Q8WXI2|CNKR2_HUMAN 22 27 GlddCL 1046 Q8WXI7|MUC16_HUMAN 22110 22115 GlitCL 1047 Q8WNK4|ASB12_HUMAN 75 80 GhlsCL 1048 Q8WXS8|ATS14_HUMAN 489 494 GyqtCL 1049 Q8WXS8|ATS14_HUMAN 587 592 GgrpCL 1050 Q8WYB5|MYST4_HUMAN 244 249 GhpsCL 1051 Q8WYP5|AHTF1_HUMAN 112 117 GsvlCL 1052 Q8WYP5|AHTF1_HUMAN 318 323 GnrkCL 1053 Q8WYP5|AHTF1_HUMAN 526 531 GynrCL 1054 Q8WZ42|TITIN_HUMAN 4919 4924 GkytCL 1055 Q8WZ42|TITIN_HUMAN 5147 5152 GsavCL 1056 Q8WZ42|TITIN_HUMAN 7829 7834 GdysCL 1057 Q8WZ42|TITIN_HUMAN 16742 16747 GaqdCL 1058 Q8WZ42|TITIN_HUMAN 20237 20242 GtnvCL 1059 Q8WZ73|RFFL_HUMAN 81 86 GprlCL 1060 Q8WZ74|CTTB2_HUMAN 924 929 GfknCL 1061 Q92481|AP2B_HUMAN 379 384 GiqsCL 1062 Q92496|FHR4_HUMAN 130 135 GsitCL 1063 Q92520|FAM3C_HUMAN 82 87 GpkiCL 1064 Q92527|ANKR7_HUMAN 148 153 GeppCL 1065 Q92529|SHC3_HUMAN 581 586 GselCL 1066 Q92546|K0258_HUMAN 248 253 GtvaCL 1067 Q92583|CCL17_HUMAN 30 35 GrecCL 1068 Q92621|NU205_HUMAN 950 955 GfveCL 1069 Q92636|FAN_HUMAN 824 829 GtdgCL 1070 Q92673|SORL_HUMAN 1415 1420 GpstCL 1071 Q92750|TAF4B_HUMAN 410 415 GaaiCL 1072 Q92752|TENR_HUMAN 293 298 GqrqCL 1073 Q92782|DPF1_HUMAN 256 261 GhpsCL 1074 Q92783|STAM1_HUMAN 41 46 GpkdCL 1075 Q92785|REQU_HUMAN 302 307 GhpsCL 1076 Q92794|MYST3_HUMAN 237 242 GhpsCL 1077 Q92832|NELL1_HUMAN 618 623 GgfdCL 1078 Q92854|SEM4D_HUMAN 620 625 GvyqCL 1079 Q92900|RENT1_HUMAN 370 375 GdeiCL 1080 Q92932|PTPR2_HUMAN 35 40 GrlgCL 1081 Q92932|PTPR2_HUMAN 634 639 GliyCL 1082 Q92947|GCDH_HUMAN 285 290 GpfgCL 1083 Q92947|GCDH_HUMAN 346 351 GlhaCL 1084 Q92952|KCNN1_HUMAN 361 366 GkgvCL 1085 Q92956|TNR14_HUMAN 89 94 GlskCL 1086 Q92968|PEX13_HUMAN 216 221 GtvaCL 1087 Q93038|TNR25_HUMAN 66 71 GnstCL 1088 Q969L2|MAL2_HUMAN 37 42 GafvCL 1089 Q969P0|IGSF8_HUMAN 402 407 GtyrCL 1090 Q96A54|ADR1_HUMAN 179 184 GavlCL 1091 Q96AP0|ACD_HUMAN 269 274 GalvCL 1092 Q96AQ2|TM125_HUMAN 71 76 GtvlCL 1093 Q96B26|EXOS8_HUMAN 230 235 GklcCL 1094 Q96B86|RGMA_HUMAN 311 316 GlylCL 1095 Q96BD0|SO4A1_HUMAN 698 703 GletCL 1096 Q96CE8|T4S18_HUMAN 8 13 GclsCL 1097 Q96CW5|GCP3_HUMAN 190 195 GvgdCL 1098 Q96D59|RN183_HUMAN 95 100 GhqlCL 1099 Q96DN5|WDR67_HUMAN 52 57 GtgdCL 1100 Q96DZ5|CLR59_HUMAN 212 217 GaakCL 1101 Q96EP1|CHFR_HUMAN 528 533 GcygCL 1102 Q96EY5|F125A_HUMAN 51 56 GyflCL 1103 Q96EZ4|MYEOV_HUMAN 232 237 GrraCL 1104 Q96F46|I17RA_HUMAN 628 633 GsgaCL 1105 Q96GC6|ZN274_HUMAN 256 261 GttcCL 1106 Q96H40|ZN486_HUMAN 132 137 GlnqCL 1107 Q96H96|COQ2_HUMAN 172 177 GvllCL 1108 Q96I82|KAZD1_HUMAN 249 254 GtyrCL 1109 Q96IV0|NGLY1_HUMAN 70 75 GaveCL 1110 Q96IW7|SC22A_HUMAN 234 239 GtaaCL 1111 Q96J02|ITCH_HUMAN 160 165 GvslCL 1112 Q96J94|PIWL1_HUMAN 674 679 GlkvCL 1113 Q96JH7|VCIP1_HUMAN 215 220 GdghCL 1114 Q96JK2|WDR22_HUMAN 178 183 GepfCL 1115 Q96JT2|S45A3_HUMAN 27 32 GlevCL 1116 Q96JT2|S45A3_HUMAN 485 490 GrgiCL 1117 Q96K31|CH076_HUMAN 98 103 GgarCL 1118 Q96KC8|DNJC1_HUMAN 228 233 GiwfCL 1119 Q96KM6|K1196_HUMAN 782 787 GkyrCL 1120 Q96LC7|SIG10_HUMAN 373 378 GqslCL 1121 Q96LD4|TRI47_HUMAN 25 30 GhnfCL 1122 Q96LQ0|CN050_HUMAN 366 371 GeprCL 1123 Q96ME1|FXL18_HUMAN 352 357 GcvhCL 1124 Q96ME7|ZN512_HUMAN 320 325 GgpeCL 1125 Q96ME7|ZN512_HUMAN 438 443 GkykCL 1126 Q96MU7|YTDC1_HUMAN 485 490 GtqlCL 1127 Q96MU8|KREM1_HUMAN 53 58 GgkpCL 1128 Q96NL3|ZN599_HUMAN 373 378 GktfCL 1129 Q96NX9|DACH2_HUMAN 585 590 GnyyCL 1130 Q96P11|NSUN5_HUMAN 400 405 GaehCL 1131 Q96PH1|NOX5_HUMAN 272 277 GcggCL 1132 Q96PL5|ERMAP_HUMAN 122 127 GsyrCL 1133 Q96PP9|GBP4_HUMAN 321 326 GavpCL 1134 Q96Q04|LMTK3_HUMAN 676 681 GacsCL 1135 Q96Q15|SMG1_HUMAN 2809 2814 GnvtCL 1136 Q96Q27|ASB2_HUMAN 101 106 GqvgCL 1137 Q96Q27|ASB2_HUMAN 135 140 GhldCL 1138 Q96Q91|B3A4_HUMAN 455 460 GaafCL 1139 Q96QG7|MTMR9_HUMAN 85 90 GmeeCL 1140 Q96QS1|TSN32_HUMAN 258 263 GpthCL 1141 Q96QU8|XPO6_HUMAN 413 418 GyfsCL 1142 Q96R30|OR2V2_HUMAN 103 108 GlfvCL 1143 Q96RV3|PCX1_HUMAN 696 701 GtvaCL 1144 Q96RW7|HMCN1_HUMAN 677 682 GiygCL 1145 Q96RW7|HMCN1_HUMAN 2546 2551 GrytCL 1146 Q96RW7|HMCN1_HUMAN 3595 3600 GrytCL 1147 Q96SM3|CPXM1_HUMAN 262 267 GgapCL 1148 Q96SQ9|CP2S1_HUMAN 436 441 GkrvCL 1149 Q96SU4|OSBL9_HUMAN 542 547 GcvsCL 1150 Q99250|SCN2A_HUMAN 955 960 GqtmCL 1151 Q99466|NOTC4_HUMAN 216 221 GsfqCL 1152 Q99466|NOTC4_HUMAN 375 380 GsfsCL 1153 Q99466|NOTC4_HUMAN 414 419 GstlCL 1154 Q99466|NOTC4_HUMAN 457 462 GsfnCL 1155 Q99466|NOTC4_HUMAN 609 614 GaffCL 1156 Q99466|NOTC4_HUMAN 787 792 GtfsCL 1157 Q99466|NOTC4_HUMAN 1121 1126 GgpdCL 1158 Q99466|NOTC4_HUMAN 1872 1877 GggaCL 1159 Q99558|M3K14_HUMAN 536 541 GhavCL 1160 Q99611|SPS2_HUMAN 373 378 GlliCL 1161 Q99678|GPR20_HUMAN 115 120 GargCL 1162 Q99741|CDC6_HUMAN 207 212 GktaCL 1163 Q99758|ABCA3_HUMAN 1590 1595 GqfkCL 1164 Q99797|PMIP_HUMAN 277 282 GqlkCL 1165 Q99848|EBP2_HUMAN 52 57 GlkqCL 1166 Q99867|TBB4Q_HUMAN 235 240 GvttCL 1167 Q99884|SC6A7_HUMAN 543 548 GllsCL 1168 Q99973|TEP1_HUMAN 1464 1469 GpfaCL 1169 Q99973|TEP1_HUMAN 1486 1491 GarlCL 1170 Q99973|TEP1_HUMAN 1720 1725 GisaCL 1171 Q99973|TEP1_HUMAN 2595 2600 GsysCL 1172 Q99996|AKAP9_HUMAN 3063 3068 GllnCL 1173 Q9BQ08|RSNB_HUMAN 2 7 GpssCL 1174 Q9BQG2|NUD12_HUMAN 348 353 GmftCL 1175 Q9BQR3|PRS27_HUMAN 231 236 GplvCL 1176 Q9BQS2|SYT15_HUMAN 23 28 GascCL 1177 Q9BRB3|PIGQ_HUMAN 373 378 GlsaCL 1178 Q9BRP4|WDR71_HUMAN 206 211 GrsaCL 1179 Q9BRZ2|TRI56_HUMAN 343 348 GpapCL 1180 Q9BS86|ZPBP1_HUMAN 346 351 GaktCL 1181 Q9BT40|SKIP_HUMAN 131 136 GvniCL 1182 Q9BT51|CU122_HUMAN 6 11 GfshCL 1183 Q9BTF0|THUM2_HUMAN 407 412 GikkCL 1184 Q9BTX1|NDC1_HUMAN 310 315 GsdeCL 1185 Q9BUY5|ZN426_HUMAN 14 19 GdpvCL 1186 Q9BUY5|ZN426_HUMAN 430 435 GypsCL 1187 Q9BV38|WDR18_HUMAN 81 86 GpvtCL 1188 Q9BV38|WDR18_HUMAN 139 144 GgkdCL 1189 Q9BV73|CP250_HUMAN 806 811 GevrCL 1190 Q9BV99|LRC61_HUMAN 113 118 GqlqCL 1191 Q9BVA1|TBB2B_HUMAN 235 240 GvttCL 1192 Q9BVH7|SIA7E_HUMAN 8 13 GlavCL 1193 Q9BVK2|ALG8_HUMAN 361 366 GflrCL 1194 Q9BWT7|CAR10_HUMAN 916 921 GkkhCL 1195 Q9BWU0|NADAP_HUMAN 185 190 GtsyCL 1196 Q9BWU0|NADAP_HUMAN 196 201 GcdvCL 1197 Q9BWV1|BOC_HUMAN 1053 1058 GppcCL 1198 Q9BXC9|BBS2_HUMAN 26 31 GthpCL 1199 Q9BXL6|CAR14_HUMAN 850 855 GfkkCL 1200 Q9BXM7|PINK1_HUMAN 408 413 GgngCL 1201 Q9BXR0|TGT_HUMAN 50 55 GcriCL 1202 Q9BXS4|TMM59_HUMAN 229 234 GfirCL 1203 Q9BXT5|TEX15_HUMAN 1099 1104 GekkCL 1204 Q9BXU8|FHL17_HUMAN 78 83 GghiCL 1205 Q9BY15|EMR3_HUMAN 562 567 GctwCL 1206 Q9BY41|HDAC8_HUMAN 283 288 GigkCL 1207 Q9BYB4|GNB1L_HUMAN 163 168 GmpmCL 1208 Q9BYE0|HES7_HUMAN 95 100 GfreCL 1209 Q9BYJ1|LOXE3_HUMAN 309 314 GqdtCL 1210 Q9BYK8|PR285_HUMAN 1908 1913 GfslCL 1211 Q9BYT1|CT059_HUMAN 398 403 GswtCL 1212 Q9BYX4|IFIH1_HUMAN 265 270 GsvsCL 1213 Q9BZ11|ADA33_HUMAN 400 405 GggaCL 1214 Q9BZ76|CNTP3_HUMAN 509 514 GfqgCL 1215 Q9BZ76|CNTP3_HUMAN 1163 1168 GftgCL 1216 Q9BZC7|ABCA2_HUMAN 2262 2267 GrlrCL 1217 Q9BZF3|OSBL6_HUMAN 554 559 GrraCL 1218 Q9BZF9|UACA_HUMAN 79 84 GnleCL 1219 Q9BZF9|UACA_HUMAN 112 117 GhalCL 1220 Q9BZH6|BRWD2_HUMAN 79 84 GspyCL 1221 Q9BZS1|FOXP3_HUMAN 228 233 GragCL 1222 Q9BZY9|TRI31_HUMAN 32 37 GhnfCL 1223 Q9BZZ2|SN_HUMAN 1507 1512 GmyhCL 1224 Q9C004|SPY4_HUMAN 197 202 GtcmCL 1225 Q9C0A0|CNTP4_HUMAN 1163 1168 GftgCL 1226 Q9C0C6|K1737_HUMAN 47 52 GsseCL 1227 Q9GZK3|OR2B2_HUMAN 108 113 GsteCL 1228 Q9GZR3|CFC1_HUMAN 144 149 GalhCL 1229 Q9GZY1|PBOV1_HUMAN 118 123 GlecCL 1230 Q9H013|ADA19_HUMAN 400 405 GggmCL 1231 Q9H093|NUAK2_HUMAN 587 592 GpgsCL 1232 Q9HA0|NAT10_HUMAN 654 659 GrfpCL 1233 Q9H0B3|K1683_HUMAN 578 583 GkirCL 1234 Q9H0J9|PAR12_HUMAN 272 277 GdgiCL 1235 Q9H0M4|ZCPW1_HUMAN 249 254 GfggCL 1236 Q9H172|ABCG4_HUMAN 588 593 GdltCL 1237 Q9H195|MUC3B_HUMAN 545 550 GqcaCL 1238 Q9H1B7|CN004_HUMAN 294 299 GgpaCL 1239 Q9H1D0|TRPV6_HUMAN 10 15 GlilCL 1240 Q9H1K4|GHC2_HUMAN 47 52 GmidCL 1241 Q9H1M3|DB129_HUMAN 23 28 GlrrCL 1242 Q9H1M4|DB127_HUMAN 50 55 GrycCL 1243 Q9H1P6|CT085_HUMAN 107 112 GlnkCL 1244 Q9H1R3|MYLK2_HUMAN 240 245 GqalCL 1245 Q9H1V8|S6A17_HUMAN 421 426 GldpCL 1246 Q9H221|ABCG8_HUMAN 421 426 GaeaCL 1247 Q9H228|EDG8_HUMAN 347 352 GlrrCL 1248 Q9H252|KCNH6_HUMAN 571 576 GfpeCL 1249 Q9H2D1|MFTC_HUMAN 64 69 GilhCL 1250 Q9H2G2|SLK_HUMAN 1208 1213 GeseCL 1251 Q9H2M9|RBGPR_HUMAN 387 392 GesiCL 1252 Q9H2S1|KCNN2_HUMAN 371 376 GkgvCL 1253 Q9H2X9|S12A5_HUMAN 602 607 GmslCL 1254 Q9H2Y7|ZF106_HUMAN 975 980 GegnCL 1255 Q9H324|ATS10_HUMAN 422 427 GlglCL 1256 Q9H324|ATS10_HUMAN 556 561 GgkyCL 1257 Q9H304|P73L_HUMAN 557 562 GcssCL 1258 Q9H3R1|NDST4_HUMAN 814 819 GktkCL 1259 Q9H4F1|SIA7D_HUMAN 29 34 GlplCL 1260 Q9H5U8|CX045_HUMAN 403 408 GfdsCL 1261 Q9H5V8|CDCP1_HUMAN 373 378 GcfvCL 1262 Q9H6E5|TUT1_HUMAN 15 20 GfrcCL 1263 Q9H6R4|NOL6_HUMAN 391 396 GislCL 1264 Q9H792|SG269_HUMAN 1661 1666 GilqCL 1265 Q9H7F0|AT133_HUMAN 109 114 GhavCL 1266 Q9H7M9|GI24_HUMAN 142 147 GlycCL 1267 Q9H808|TLE6_HUMAN 315 320 GpdaCL 1268 Q9H8X2|IPPK_HUMAN 110 115 GyamCL 1269 Q9H9S3|S61A2_HUMAN 143 148 GagiCL 1270 Q9HAF5|CO028_HUMAN 120 125 GvrmCL 1271 Q9HAS0|NJMU_HUMAN 123 128 GcyyCL 1272 Q9HAT1|LMA1L_HUMAN 8 13 GplfCL 1273 Q9HAV4|XPO5_HUMAN 266 271 GaaeCL 1274 Q9HAW7|UD17_HUMAN 510 515 GyrkCL 1275 Q9HAW8|UD110_HUMAN 510 515 GyrkCL 1276 Q9HAW9|UD18_HUMAN 510 515 GyrkCL 1277 Q9HBX8|LGR6_HUMAN 550 555 GvlgCL 1278 Q9HBZ2|ARNT2_HUMAN 295 300 GskyCL 1279 Q9HC07|TM165_HUMAN 138 143 GlmtCL 1280 Q9HC84|MUC5B_HUMAN 780 785 GklsCL 1281 Q9HC84|MUC5B_HUMAN 1281 1286 GlgaCL 1282 Q9HCC6|HES4_HUMAN 113 118 GfheCL 1283 Q9HCC9|ZFY28_HUMAN 555 560 GatnCL 1284 Q9HCE9|TM16H_HUMAN 541 546 GgrrCL 1285 Q9HCM2|PLXA4_HUMAN 990 995 GkqpCL 1286 Q9HCM4|E41L5_HUMAN 111 116 GspyCL 1287 Q9HCU4|CELR2_HUMAN 1308 1313 GgytCL 1288 Q9HCU4|CELR2_HUMAN 1757 1762 GfrgCL 1289 Q9HCU4|CELR2_HUMAN 1917 1922 GsptCL 1290 Q9NNW5|WDR6_HUMAN 460 465 GvvaCL 1291 Q9NP73|GT281_HUMAN 82 87 GagsCL 1292 Q9NP90|RAB9B_HUMAN 79 84 GadcCL 1293 Q9NPA1|KCMB3_HUMAN 121 126 GkypCL 1294 Q9NPA3|M1IP1_HUMAN 58 63 GsggCL 1295 Q9NPD7|NRN1_HUMAN 37 42 GfsdCL 1296 Q9NPF8|CENA2_HUMAN 41 46 GifiCL 1297 Q9NPG4|PCD12_HUMAN 807 812 GwdpCL 1298 Q9NPH5|NOX4_HUMAN 51 56 GlglCL 1299 Q9NQ25|SLAF7_HUMAN 3 8 GsptCL 1300 Q9NQ30|ESM1_HUMAN 125 130 GtgkCL 1301 Q9NQ75|CT032_HUMAN 50 55 GwwkCL 1302 Q9NQB0|TF7L2_HUMAN 492 497 GegsCL 1303 Q9NQQ7|S35C2_HUMAN 302 307 GfalCL 1304 Q9NQS5|GPR84_HUMAN 195 200 GifyCL 1305 Q9NQU5|PAK6_HUMAN 662 667 GlpeCL 1306 Q9NR09|BIRC6_HUMAN 511 516 GanpCL 1307 Q9NR61|DLL4_HUMAN 204 209 GnlsCL 1308 Q9NR63|CP26B_HUMAN 437 442 GvrtCL 1309 Q9NR81|ARHG3_HUMAN 203 208 GwlpCL 1310 Q9NR99|MXRA5_HUMAN 2414 2419 GnytCL 1311 Q9NR15|DISC1_HUMAN 23 28 GsrdCL 1312 Q9NRX5|SERC1_HUMAN 19 24 GsapCL 1313 Q9NS15|LTBP3_HUMAN 846 851 GsyrCL 1314 Q9NS40|KCNH7_HUMAN 722 727 GfpeCL 1315 Q9NS62|THSD1_HUMAN 419 424 GislCL 1316 Q9NSD7|RL3R1_HUMAN 243 248 GeelCL 1317 Q9NS16|BRWD1_HUMAN 204 209 GsddCL 1318 Q9NSN8|SNTG1_HUMAN 242 247 GiigCL 1319 Q9NST1|ADPN_HUMAN 24 29 GatrCL 1320 Q9NST1|ADPN_HUMAN 97 102 GlckCL 1321 Q9NT68|TEN2_HUMAN 858 863 GlvdCL 1322 Q9NU22|MDN1_HUMAN 427 432 GrgdCL 1323 Q9NUB4|CT141_HUMAN 156 161 GlafCL 1324 Q9NUP1|CNO_HUMAN 67 72 GyaaCL 1325 Q9NVE7|PANK4_HUMAN 304 309 GglaCL 1326 Q9NVG8|TBC13_HUMAN 38 43 GglrCL 1327 Q9NVX2|NLE1_HUMAN 474 479 GkdkCL 1328 Q9NW08|RPC2_HUMAN 765 770 GfgrCL 1329 Q9NWT1|PK1IP_HUMAN 83 88 GtitCL 1330 Q9NWU5|RM22_HUMAN 142 147 GrggCL 1331 Q9NWZ3|IRAK4_HUMAN 255 260 GddlCL 1332 Q9NX02|NALP2_HUMAN 139 144 GnviCL 1333 Q9NXJ0|M4A12_HUMAN 106 111 GivlCL 1334 Q9NXR5|ANR10_HUMAN 69 74 GkleCL 1335 Q9NXR5|ANR10_HUMAN 103 108 GhpqCL 1336 Q9NXS3|BTBD5_HUMAN 293 298 GlfaCL 1337 Q9NXW9|ALKB4_HUMAN 19 24 GirtCL 1338 Q9NY15|STAB1_HUMAN 122 127 GhgtCL 1339 Q9NY15|STAB1_HUMAN 177 182 GdgsCL 1340 Q9NY15|STAB1_HUMAN 752 757 GngaCL 1341 Q9NY15|STAB1_HUMAN 1256 1261 GssrCL 1342 Q9NY15|STAB1_HUMAN 1991 1996 GsggCL 1343 Q9NY15|STAB1_HUMAN 2250 2255 GfhlCL 1344 Q9NY33|DPP3_HUMAN 515 520 GlylCL 1345 Q9NY35|CLDND_HUMAN 213 218 GwsfCL 1346 Q9NY46|SCN3A_HUMAN 956 961 GqtmCL 1347 Q9NY91|SC5A4_HUMAN 507 512 GtgsCL 1348 Q9NY99|SNTG2_HUMAN 14 19 GrqgCL 1349 Q9NYJ7|DLL3_HUMAN 235 240 GecrCL 1350 Q9NYQ6|CELR1_HUMAN 168 173 GrpiCL 1351 Q9NYQ7|CELR3_HUMAN 2070 2075 GsdsCL 1352 Q9NYQ8|FAT2_HUMAN 3908 3913 GfegCL 1353 Q9NYQ8|FAT2_HUMAN 4285 4290 GggpCL 1354 Q9NYW6|TA2R3_HUMAN 104 109 GvlyCL 1355 Q9NZ56|FMN2_HUMAN 1694 1699 GkegCL 1356 Q9NZ71|RTEL1_HUMAN 47 52 GktlCL 1357 Q9NZ94|NLGN3_HUMAN 19 24 GrslCL 1358 Q9NZH0|GPC5B_HUMAN 164 169 GlalCL 1359 Q9NZH7|IL1F8_HUMAN 68 73 GkdlCL 1360 Q9NZL3|ZN224_HUMAN 550 555 GwasCL 1361 Q9NZR2|LRP1B_HUMAN 866 871 GdddCL 1362 Q9NZR2|LRP1B_HUMAN 2987 2992 GtykCL 1363 Q9NZV5|SEPN1_HUMAN 273 278 GavaCL 1364 Q9POK1|ADA22_HUMAN 429 434 GggaCL 1365 Q9P0K7|RAI14_HUMAN 64 69 GhveCL 1366 Q9P0L1|ZN167_HUMAN 617 622 GlskCL 1367 Q9P0M9|RM27_HUMAN 84 89 GknkCL 1368 Q9P0U3|SENP1_HUMAN 531 536 GvhwCL 1369 Q9P0X4|CAC1I_HUMAN 290 295 GrecCL 1370 Q9P203|BTBD7_HUMAN 265 270 GnqnCL 1371 Q9P255|ZN492_HUMAN 143 148 GlnqCL 1372 Q9P273|TEN3_HUMAN 142 147 GrssCL 1373 Q9P273|TEN3_HUMAN 1590 1595 GtngCL 1374 Q9P275|UBP36_HUMAN 824 829 GsetCL 1375 Q9P283|SEM5B_HUMAN 589 594 GgldCL 1376 Q9P283|SEM5B_HUMAN 887 892 GediCL 1377 Q9P298|HIG1B_HUMAN 34 39 GlggCL 1378 Q9P2B2|FPRP_HUMAN 844 849 GllsCL 1379 Q9P2C4|TM181_HUMAN 406 411 GerkCL 1380 Q9P2E3|ZNFX1_HUMAN 1162 1167 GqlfCL 1381 Q9P2I0|CPSF2_HUMAN 759 764 GlegCL 1382 Q9P2J9|PDP2_HUMAN 125 130 GvasCL 1383 Q9P2J9|PDP2_HUMAN 298 303 GmwsCL 1384 Q9P2N4|ATS9_HUMAN 490 495 GygeCL 1385 Q9P2P6|STAR9_HUMAN 715 720 GeadCL 1386 Q9P2R3|ANFY1_HUMAN 720 725 GpggCL 1387 Q9P2R7|SUCB1_HUMAN 316 321 GnigCL 1388 Q9P2S2|NRX2A_HUMAN 1061 1066 GfqgCL 1389 Q9UBD9|CLCF1_HUMAN 10 15 GmlaCL 1390 Q9UBE0|ULE1A_HUMAN 338 343 GiveCL 1391 Q9UBG0|MRC2_HUMAN 50 55 GlqgCL 1392 Q9UBG0|MRC2_HUMAN 89 94 GtmgCL 1393 Q9UBG0|MRC2_HUMAN 938 943 GdqrCL 1394 Q9UBG7|RBPSL_HUMAN 56 61 GvrrCL 1395 Q9UBG7|RBPSL_HUMAN 326 331 GtylCL 1396 Q9UBH0|IL1F5_HUMAN 63 68 GgsgCL 1397 Q9UBM4|OPT_HUMAN 124 129 GlptCL 1398 Q9UBP5|HEY2_HUMAN 125 130 GfreCL 1399 Q9UBS8|RNF14_HUMAN 258 263 GqvgCL 1400 Q9UBY5|EDG7_HUMAN 37 42 GtffCL 1401 Q9UBY8|CLN8_HUMAN 145 150 GflgCL 1402 Q9UDX3|S14L4_HUMAN 250 255 GnpkCL 1403 Q9UDX3|S14L4_HUMAN 351 356 GsltCL 1404 Q9UDX4|S14L3_HUMAN 250 255 GnpkCL 1405 Q9UGF7|O12D3_HUMAN 62 67 GnlsCL 1406 Q9UG16|KCNN3_HUMAN 525 530 GkgvCL 1407 Q9UGU5|HM2L1_HUMAN 567 572 GplaCL 1408 Q9UHA7|IL1F6_HUMAN 69 74 GlnlCL 1409 Q9UHC6|CNTP2_HUMAN 1174 1179 GftgCL 1410 Q9UHD0|IL19_HUMAN 24 29 GlrrCL 1411 Q9UH18|ATS1_HUMAN 458 463 GhgeCL 1412 Q9UHW9|S12A6_HUMAN 687 692 GmsiCL 1413 Q9UHX3|EMR2_HUMAN 742 747 GctwCL 1414 Q9U1A9|XPO7_HUMAN 933 938 GccsCL 1415 Q9U1E0|ZN230_HUMAN 286 291 GksfCL 1416 Q9U1F8|BAZ2B_HUMAN 627 632 GmqwCL 1417 Q9U1F9|BAZ2A_HUMAN 1006 1011 GpeeCL 1418 Q9U1H9|KLF15_HUMAN 117 122 GehfCL 1419 Q9UIR0|BTNL2_HUMAN 337 342 GgyrCL 1420 Q9UK10|ZN225_HUMAN 466 471 GwasCL 1421 Q9UK11|ZN223_HUMAN 294 299 GksfCL 1422 Q9UK12|ZN222_HUMAN 263 268 GksfCL 1423 Q9UK13|ZN221_HUMAN 488 493 GwasCL 1424 Q9UK13|ZN221_HUMAN 572 577 GwasCL 1425 Q9UK99|FBX3_HUMAN 189 194 GlkyCL 1426 Q9UKB1|FBW1B_HUMAN 281 286 GsvlCL 1427 Q9UKP4|ATS7_HUMAN 443 448 GwglCL 1428 Q9UKP5|ATS6_HUMAN 545 550 GgkyCL 1429 Q9UKQ2|ADA28_HUMAN 500 505 GkghCL 1430 Q9UKU0|ACSL6_HUMAN 104 109 GngpCL 1431 Q9UL25|RAB21_HUMAN 121 126 GneiCL 1432 Q9ULB1|NRX1A_HUMAN 1048 1053 GfqgCL 1433 Q9ULL4|PLXB3_HUMAN 1191 1196 GrgeCL 1434 Q9ULV0|MYO5B_HUMAN 1496 1501 GtvpCL 1435 Q9UM47|NOTC3_HUMAN 1228 1233 GgfrCL 1436 Q9UM82|SPAT2_HUMAN 37 42 GsdeCL 1437 Q9UMF0|ICAM5_HUMAN 879 884 GeavCL 1438 Q9UMW8|UBP18_HUMAN 61 66 GqtcCL 1439 Q9UNA0|ATS5_HUMAN 467 472 GhgnCL 1440 Q9UNA0|ATS5_HUMAN 525 530 GqmvCL 1441 Q9UNI1|ELA1_HUMAN 208 213 GplhCL 1442 Q9UP79|ATS8_HUMAN 421 426 GhgdCL 1443 Q9UP79|ATS8_HUMAN 562 567 GgryCL 1444 Q9UP95|S12A4_HUMAN 622 627 GmslCL 1445 Q9UPA5|BSN_HUMAN 1765 1770 GspvCL 1446 Q9UPZ6|THS7A_HUMAN 881 886 GiheCL 1447 Q9UQ05|KCNH4_HUMAN 213 218 GgsrCL 1448 Q9UQ49|NEUR3_HUMAN 380 385 GlfgCL 1449 Q9UQ52|CNTN6_HUMAN 96 101 GmyqCL 1450 Q9UQD0|SCN8A_HUMAN 949 954 GqamCL 1451 Q9Y219|JAG2_HUMAN 907 912 GwkpCL 1452 Q9Y236|OSGI2_HUMAN 480 485 GvtrCL 1453 Q9Y263|PLAP_HUMAN 721 726 GkagCL 1454 Q9Y278|OST2_HUMAN 51 56 GaprCL 1455 Q9Y297|FBW1A_HUMAN 344 349 GsvlCL 1456 Q9Y2H6|FNDC3_HUMAN 790 795 GivtCL 1457 Q9Y2L6|FRM4B_HUMAN 871 876 GsgrCL 1458 Q9Y2P5|S27A5_HUMAN 345 350 GilgCL 1459 Q9Y2P5|S27A5_HUMAN 452 457 GkmsCL 1460 Q9Y2Q1|ZN257_HUMAN 132 137 GlnqCL 1461 Q9Y2T5|GPR52_HUMAN 205 210 GfivCL 1462 Q9Y385|UB2J1_HUMAN 87 92 GkkiCL 1463 Q9Y3B6|CN122_HUMAN 38 43 GeclCL 1464 Q9Y3C8|UFC1_HUMAN 112 117 GgkiCL 1465 Q9Y3I1|FBX7_HUMAN 71 76 GdliCL 1466 Q9Y3N9|OR2W1_HUMAN 108 113 GsveCL 1467 Q9Y3R4|NEUR2_HUMAN 160 165 GpghCL 1468 Q9Y3S2|ZN330_HUMAN 182 187 GqhsCL 1469 Q9Y485|DMXL1_HUMAN 187 192 GkddCL 1470 Q9Y485|DMXL1_HUMAN 2862 2867 XrnvCL 1471 Q9Y493|ZAN_HUMAN 1152 1157 GtatCL 1472 Q9Y4C0|NRX3A_HUMAN 1014 1019 GfqgCL 1473 Q9Y4F1|FARP1_HUMAN 820 825 GvphCL 1474 Q9Y4K1|AIM1_HUMAN 1473 1478 GhypCL 1475 Q9Y4W6|AFG32_HUMAN 31 36 GeqpCL 1476 Q9Y535|RPC8_HUMAN 43 48 GlciCL 1477 Q9Y561|LRP12_HUMAN 241 246 GnidCL 1478 Q9Y574|ASB4_HUMAN 86 91 GhveCL 1479 Q9Y575|ASB3_HUMAN 291 296 GhedCL 1480 Q9Y5F7|PCDGL_HUMAN 729 734 GtcaCL 1481 Q9Y5J3|HEY1_HUMAN 126 131 GfreCL 1482 Q9Y5N5|HEMK2_HUMAN 45 50 GveiCL 1483 Q9Y5Q5|CORIN_HUMAN 424 429 GdqrCL 1484 Q9Y5R5|DMRT2_HUMAN 130 135 GvvsCL 1485 Q9Y5R6|DMRT1_HUMAN 153 158 GsnpCL 1486 Q9Y5S2|MRCKB_HUMAN 1374 1379 GsvgCL 1487 Q9Y5W8|SNX13_HUMAN 73 78 GvpkCL 1488 Q9Y616|IRAK3_HUMAN 395 400 GldsCL 1489 Q9Y644|RFNG_HUMAN 203 208 GagfCL 1490 Q9Y662|0S13B_HUMAN 7 12 GgrsCL 1491 Q9Y666|S12A7_HUMAN 622 627 GmslCL 1492 Q9Y6H5|SNCAP_HUMAN 361 366 GhaeCL 1493 Q9Y614|UBP3_HUMAN 449 454 GpesCL 1494 Q9Y6N6|LAMC3_HUMAN 885 890 GqcsCL 1495 Q9Y6R1|S4A4_HUMAN 512 517 GaifCL 1496 Q9Y6R7|FCGBP_HUMAN 1661 1666 GqgvCL 1497 Q9Y6R7|FCGBP_HUMAN 2388 2393 GqcgCL 1498 Q9Y6R7|FCGBP_HUMAN 2862 2867 GqgvCL 1499 Q9Y6R7|FCGBP_HUMAN 3589 3594 GqcgCL 1500 Q9Y6R7|FCGBP_HUMAN 4063 4068 GqgvCL 1501 Q9Y6R7|FCGBP_HUMAN 4790 4795 GqcgCL 1502 Q9Y6R7|FCGBP_HUMAN 4852 4857 GcgrCL 1503 Q9Y6R7|FCGBP_HUMAN 5032 5037 GcpvCL

TABLE 5 Collagens Motif: C-N-X(3)-V-C (SEQ ID NO: 2487) Number of Locations: 24 Number of Different Proteins: 24 SEQ Accession First Last ID Number|Protein Amino Amino NO: Name acid acid Sequence 1504 O14514|BA11_HUMAN 400 406 CNnsaVC 1505 O75093|SLIT1_HUMAN 507 513 CNsdvVC 1506 O75534|CSDE1_HUMAN 733 739 CNvwrVC 1507 P02462|CO4A1_HUMAN 1505 1511 CNinnVC 1508 P08572|CO4A2_HUMAN 1549 1555 CNpgdVC 1509 P09758|TACD2_HUMAN 119 125 CNqtsVC 1510 P25391|LAMA1_HUMAN 751 757 CNvhgVC 1511 P29400|CO4A5_HUMAN 1521 1527 CNinnVC 1512 P53420|CO4A4_HUMAN 1525 1531 CNihqVC 1513 P83110|HTRA3_HUMAN 48 54 CNcclVC 1514 Q01955|CO4A3_HUMAN 1505 1511 CNvndVC 1515 Q13625|ASPP2_HUMAN 1002 1008 CNnvqVC 1516 Q13751|LAMB3_HUMAN 572 578 CNrypVC 1517 Q14031|CO4A6_HUMAN 1527 1533 CNineVC 1518 Q8WWQ8|STAB2_HUMAN 1970 1976 CNnrgVC 1519 Q96GX1|TECT2_HUMAN 642 648 CNrneVC 1520 Q99965|ADAM2_HUMAN 621 627 CNdrgVC 1521 Q9BX93|PG12B_HUMAN 112 118 CNqldVC 1522 Q9BYD5|CNFN_HUMAN 32 38 CNdmpVC 1523 Q9H013|ADA19_HUMAN 659 665 CNghgVC 1524 Q9HBG6|IF122_HUMAN 436 442 CNllvVC 1525 Q9P2R7|SUCB1_HUMAN 152 158 CNqvlVC 1526 Q9UBX1|CATF_HUMAN 89 95 CNdpmVC 1527 Q9UKF2|ADA30_HUMAN 638 644 CNtrgVC

TABLE 6 Collagens Motif: P-F-X2-C Number of Locations: 306 Number of Different Proteins: 288 SEQ Accession First Last ID Number|Protein Amino Amino NO: Name acid acid Sequence 1528 O00116|ADAS_HUMAN 561 565 PFstC 1529 O00182|LEG9_HUMAN 98 102 PFdlC 1530 O00206|TLR4_HUMAN 702 706 PFqlC 1531 O00270|GPR31_HUMAN 2 6 PFpnC 1532 O00398|P2Y10_HUMAN 288 292 PFclC 1533 O00507|USP9Y_HUMAN 259 263 PFgqC 1534 O14646|CHD1_HUMAN 450 454 PFkdC 1535 O14843|FFAR3_HUMAN 84 88 PFilC 1536 O14978|ZN263_HUMAN 547 551 PFseC 1537 O15015|ZN646_HUMAN 880 884 PFlcC 1538 O15031|PLXB2_HUMAN 611 615 PFydC 1539 O15037|K0323_HUMAN 423 427 PFtlC 1540 O15453|NBR2_HUMAN 9 13 PFlpC 1541 O15529|GPR42_HUMAN 84 88 PFilC 1542 O43556|SGCE_HUMAN 207 211 PFssC 1543 O60299|K0552_HUMAN 308 312 PFaaC 1544 O60343|TBCD4_HUMAN 89 93 PFlrC 1545 O60431|OR1I1_HUMAN 93 97 PFvgC 1546 O60449|LY75_HUMAN 1250 1254 PFqnC 1547 O60481|ZIC3_HUMAN 331 335 PFpgC 1548 O60486|PLXC1_HUMAN 618 622 PFtaC 1549 O60494|CUBN_HUMAN 3302 3306 PFsiC 1550 O60603|TLR2_HUMAN 669 673 PFklC 1551 O60656|UD19_HUMAN 149 153 PFdnC 1552 O60706|ABCC9_HUMAN 627 631 PFesC 1553 O75152|ZC11A_HUMAN 23 27 PFrhC 1554 O75197|LRP5_HUMAN 317 321 PFytC 1555 O75419|CC45L_HUMAN 444 448 PFlyC 1556 O75473|LGR5_HUMAN 547 551 PFkpC 1557 O75478|TAD2L_HUMAN 38 42 PFflC 1558 O75581|LRP6_HUMAN 304 308 PFyqC 1559 O75794|CD123_HUMAN 147 151 PFihC 1560 O75882|ATRN_HUMAN 969 973 PFgqC 1561 O76031|CLPX_HUMAN 313 317 PFaiC 1562 O95006|OR2F2_HUMAN 93 97 PFqsC 1563 O95007|OR6B1_HUMAN 285 289 PFiyC 1564 O95149|SPN1_HUMAN 195 199 PFydC 1565 O95202|LETM1_HUMAN 51 55 PFgcC 1566 O95409|ZIC2_HUMAN 336 340 PFpgC 1567 O95450|ATS2_HUMAN 569 573 PFgsC 1568 O95759|TBCD8_HUMAN 67 71 PFsrC 1569 O95841|ANGL1_HUMAN 276 280 PFkdC 1570 O95886|DLGP3_HUMAN 98 102 PFdtC 1571 P02461|CO3A1_HUMAN 80 84 PFgeC 1572 P02462|CO4A1_HUMAN 1501 1505 PFIfC 1573 P02462|CO4A1_HUMAN 1612 1616 PFieC 1574 P08151|GLI1_HUMAN 173 177 PFptC 1575 P08572|CO4A2_HUMAN 1545 1549 PFlyC 1576 P08572|CO4A2_HUMAN 1654 1658 PFieC 1577 P08581|MET_HUMAN 534 538 PFvqC 1578 P09172|DOPO_HUMAN 136 140 PFgtC 1579 P0C0L4|CO4A_HUMAN 731 735 PFIsC 1580 P0C0L5|CO4B_HUMAN 731 735 PFIsC 1581 P15309|PPAP_HUMAN 157 161 PFrnC 1582 P17021|ZNF17_HUMAN 350 354 PFycC 1583 P180841|ITB5_HUMAN 546 550 PFceC 1584 P20645|MPRD_HUMAN 3 7 PFysC 1585 P20851|C4BB_HUMAN 130 134 PFpiC 1586 P20933|ASPG_HUMAN 13 17 PFllC 1587 P21673|SAT1_HUMAN 50 54 PFyhC 1588 P21854|CD72_HUMAN 222 226 PFftC 1589 P22309|UD11_HUMAN 152 156 PFlpC 1590 P22362|CCL1_HUMAN 29 33 PFsrC 1591 P22681|CBL_HUMAN 417 421 PFcrC 1592 P23942|RDS_HUMAN 210 214 PFscC 1593 P24043|LAMA2_HUMAN 2679 2683 PFegC 1594 P24043|LAMA2_HUMAN 3083 3087 PFrgC 1595 P24903|CP2F1_HUMAN 483 487 PFqlC 1596 P25098|ARBK1_HUMAN 252 256 PFivC 1597 P25490|TYY1_HUMAN 386 390 PFdgC 1598 P25929|NPY1R_HUMAN 117 121 PFvqC 1599 P26718|NKG2D_HUMAN 52 56 PFffC 1600 P26927|HGFL_HUMAN 439 443 PFdyC 1601 P27987|IP3KB_HUMAN 869 873 PFfkC 1602 P29400|CO4A5_HUMAN 1517 1521 PFmfC 1603 P29400|CO4A5_HUMAN 1628 1632 PFieC 1604 P34896|GLYC_HUMAN 244 248 PFehC 1605 P35504|UD15_HUMAN 153 157 PFhlC 1606 P35523|CLCN1_HUMAN 26 30 PFehC 1607 P35626|ARBK2_HUMAN 252 256 PFivC 1608 P36383|CXA7_HUMAN 205 209 PFyvC 1609 P36508|ZNF76_HUMAN 258 262 PFegC 1610 P36509|UD12_HUMAN 149 153 PFdnC 1611 P36894|BMR1A_HUMAN 57 61 PFlkC 1612 P41180|CASR_HUMAN 538 542 PFsnC 1613 P42338|PK3CB_HUMAN 650 654 PFldC 1614 P42575|CASP2_HUMAN 141 145 PFpvC 1615 P45974|UBP5_HUMAN 528 532 PFssC 1616 P46531|NOTC1_HUMAN 1411 1415 PFyrC 1617 P48637|GSHB_HUMAN 405 409 PFenC 1618 P49257|LMAN1_HUMAN 471 475 PFpsC 1619 P49888|ST1E1_HUMAN 79 83 PFleC 1620 P50052|AGTR2_HUMAN 315 319 PFlyC 1621 P50876|UB714_HUMAN 273 277 PFvlC 1622 P51606|RENBP_HUMAN 376 380 PFkgC 1623 P51617|IRAK1_HUMAN 195 199 PFpfC 1624 P51689|ARSD_HUMAN 581 585 PFcsC 1625 P51690|ARSE_HUMAN 576 580 PFplC 1626 P52740|ZN132_HUMAN 369 373 PFecC 1627 P52747|ZN143_HUMAN 318 322 PFegC 1628 P53420|CO4A4_HUMAN 1521 1525 PFayC 1629 P53420|CO4A4_HUMAN 1630 1634 PFleC 1630 P53621|COPA_HUMAN 1165 1169 PFdiC 1631 P54198|HIRA_HUMAN 215 219 PFdeC 1632 P54793|ARSF_HUMAN 570 574 PFclC 1633 P54802|ANAG_HUMAN 401 405 PFiwC 1634 P55157|MTP_HUMAN 823 827 PFlvC 1635 P62079|TSN5_HUMAN 183 187 PFscC 1636 P78357|CNTP1_HUMAN 926 930 PFvgC 1637 P78527|PRKDC_HUMAN 2853 2857 PFvsC 1638 P81133|SIM1_HUMAN 200 204 PFdgC 1639 P98088|MUC5A_HUMAN 290 294 PFkmC 1640 Q01955|CO4A3_HUMAN 1501 1505 PFlfC 1641 Q01955|CO4A3_HUMAN 1612 1616 PFleC 1642 Q02817|MUC2_HUMAN 597 601 PFgrC 1643 Q02817|MUC2_HUMAN 1375 1379 PFglC 1644 Q02817|MUC2_HUMAN 4916 4920 PFywC 1645 Q03395|ROM1_HUMAN 213 217 PFscC 1646 Q07912|ACK1_HUMAN 293 297 PFawC 1647 Q12830|BPTF_HUMAN 2873 2877 PFyqC 1648 Q12836|ZP4_HUMAN 238 242 PFtsC 1649 Q12866|MERTK_HUMAN 313 317 PFrnC 1650 Q12950|FOXD4_HUMAN 291 295 PFpcC 1651 Q12968|NFAC3_HUMAN 327 331 PFqyC 1652 Q13191|CBLB_HUMAN 409 413 PFcrC 1653 Q13258|PD2R_HUMAN 4 8 PFyrC 1654 Q13356|PPIL2_HUMAN 38 42 PFdhC 1655 Q13607|OR2F1_HUMAN 93 97 PFqsC 1656 Q13753|LAMC2_HUMAN 409 413 PFgtC 1657 Q13936|CAC1C_HUMAN 2179 2183 PFvnC 1658 Q14031|CO4A6_HUMAN 1523 1527 PFiyC 1659 Q14031|CO4A6_HUMAN 1632 1636 PFieC 1660 Q14137|BOP1_HUMAN 400 404 PFptC 1661 Q14330|GPR18_HUMAN 247 251 PFhiC 1662 Q14643|ITPR1_HUMAN 526 530 PFtdC 1663 Q15042|RB3GP_HUMAN 267 271 PFgaC 1664 Q15389|ANGP1_HUMAN 282 286 PFrdC 1665 Q15583|TGIF_HUMAN 269 273 PFhsC 1666 Q15583|TGIF_HUMAN 314 318 PFslC 1667 Q15761|NPY5R_HUMAN 128 132 PFlqC 1668 Q15915|ZIC1_HUMAN 305 309 PFpgC 1669 Q16363|LAMA4_HUMAN 1788 1792 PFtgC 1670 Q16572|VACHT_HUMAN 517 521 PFdeC 1671 Q16586|SGCA_HUMAN 205 209 PFstC 1672 Q16773|KAT1_HUMAN 123 127 PFfdC 1673 Q16878|CDO1_HUMAN 160 164 PFdtC 1674 Q2TBC4|CF049_HUMAN 298 302 PFstC 1675 Q49AM1|MTER3_HUMAN 28 32 PFlaC 1676 Q53FE4|CD017_HUMAN 77 81 PFanC 1677 Q53G59|KLH12_HUMAN 240 244 PFirC 1678 Q53T03|RBP22_HUMAN 517 521 PFpvC 1679 Q51J48|CRUM2_HUMAN 762 766 PFrgC 1680 Q5T442|CXA12_HUMAN 241 245 PFfpC 1681 Q5VYX0|RENAL_HUMAN 310 314 PFlaC 1682 Q5W0N0|CI057_HUMAN 89 93 PFhgC 1683 Q6NSW7|NANP8_HUMAN 239 243 PFynC 1684 Q6P2Q9|PRP8_HUMAN 1892 1896 PFgaC 1685 Q6PRD1|GP179_HUMAN 232 236 PFleC 1686 Q6TCH4|PAQR6_HUMAN 95 99 PFasC 1687 Q6UB98|ANR12_HUMAN 1949 1953 PFsaC 1688 Q6UB99|ANR11_HUMAN 2552 2556 PFsaC 1689 Q6UXZ4|UNC5D_HUMAN 766 770 PFtaC 1690 Q7Z434|MAVS_HUMAN 431 435 PFsgC 1691 Q7Z6J6|FRMD5_HUMAN 87 91 PFtmC 1692 Q7Z7G8|VP13B_HUMAN 441 445 PFfdC 1693 Q7Z7G8|VP13B_HUMAN 1423 1427 PFrnC 1694 Q7Z7M1|GP144_HUMAN 352 356 PFlcC 1695 Q86SJ6|DSG4_HUMAN 523 527 PFtfC 1696 Q86SQ6|GP123_HUMAN 863 867 PFiiC 1697 Q86T65|DAAM2_HUMAN 548 552 PFacC 1698 Q86V97|KBTB6_HUMAN 355 359 PFlcC 1699 Q86XI2|CNDG2_HUMAN 1043 1047 PFsrC 1700 Q86YT6|MIB1_HUMAN 909 913 PFimC 1701 Q8IUH2|CREG2_HUMAN 152 156 PFgnC 1702 Q8IWU5|SULF2_HUMAN 745 749 PFcaC 1703 Q8IWV8|UBR2_HUMAN 1514 1518 PFlkC 1704 Q8IWX5|SGPP2_HUMAN 257 261 PFflC 1705 Q8IX07|FOG1_HUMAN 293 297 PFpqC 1706 Q81X29|FBX16_HUMAN 287 291 PFplC 1707 Q8IXT2|DMRTD_HUMAN 224 228 PFttC 1708 Q81ZF5|GP113_HUMAN 62 66 PFpaC 1709 Q8IZQ8|MYCD_HUMAN 403 407 PFqdC 1710 Q81ZW8|TENS4_HUMAN 423 427 PFttC 1711 Q8N0W3|FUK_HUMAN 100 104 PFddC 1712 Q8N122|RPTOR_HUMAN 1033 1037 PFtpC 1713 Q8N1G1|REXO1_HUMAN 278 282 PFgsC 1714 Q8N1G2|K0082_HUMAN 790 794 PFhiC 1715 Q8N201|INT1_HUMAN 1573 1577 PFpaC 1716 Q8N475|FSTL5_HUMAN 61 65 PFgsC 1717 Q8N567|ZCHC9_HUMAN 182 186 PFakC 1718 Q8N7R0|NANG2_HUMAN 166 170 PFynC 1719 Q8N8U9|BMPER_HUMAN 234 238 PFgsC 1720 Q8N9L1|ZIC4_HUMAN 207 211 PFpgC 1721 Q8NB16|MLKL_HUMAN 411 415 PFqgC 1722 Q8NG11|TSN14_HUMAN 183 187 PFscC 1723 Q8NGC3|O10G2_HUMAN 98 102 PFggC 1724 Q8NGC4|O10G3_HUMAN 94 98 PFggC 1725 Q8NGJ1|OR4D6_HUMAN 165 169 PFpfC 1726 Q8NH69|OR5W2_HUMAN 93 97 PFygC 1727 Q8NH85|OR5R1_HUMAN 93 97 PFhaC 1728 Q8NHU2|CT026_HUMAN 442 446 PFntC 1729 Q8NHY3|GA2L2_HUMAN 359 363 PFlrC 1730 Q8N151|BORIS_HUMAN 369 373 PFqcC 1731 Q8TCB0|IFI44_HUMAN 246 250 PFilC 1732 Q8TCE9|PPL13_HUMAN 88 92 PFelC 1733 Q8TCT7|PSL1_HUMAN 275 279 PFgkC 1734 Q8TD94|KLF14_HUMAN 198 202 PFpgC 1735 Q8TF76|HASP_HUMAN 474 478 PFshC 1736 Q8WW14|CJ082_HUMAN 22 26 PFlsC 1737 Q8WW38|FOG2_HUMAN 299 303 PFpqC 1738 Q8WWG1|NRG4_HUMAN 32 36 PFcrC 1739 Q8WWZ7|ABCA5_HUMAN 361 365 PFchC 1740 Q8WXT5|FX4L4_HUMAN 295 299 PFpcC 1741 Q8WYR1|PI3R5_HUMAN 814 818 PFavC 1742 Q8WZ42|TITIN_HUMAN 31091 31095 PFpiC 1743 Q8WZ60|KLHL6_HUMAN 432 436 PFhnC 1744 Q92485|ASM3B_HUMAN 41 45 PFqvC 1745 Q92793|CBP_HUMAN 1279 1283 PFvdC 1746 Q92838|EDA_HUMAN 328 332 PFlqC 1747 Q92995|UBP13_HUMAN 540 544 PFsaC 1748 Q93008|USP9X_HUMAN 251 255 PFgqC 1749 Q96F10|SAT2_HUMAN 50 54 PFyhC 1750 Q96FV3|TSN17_HUMAN 185 189 PFscC 1751 Q96IK0|TM101_HUMAN 27 31 PFwgC 1752 Q96L50|LLR1_HUMAN 344 348 PFhlC 1753 Q96L73|NSD1_HUMAN 456 460 PFedC 1754 Q96P88|GNRR2_HUMAN 184 188 PFtqC 1755 Q96PZ7|CSMD1_HUMAN 2139 2143 PFprC 1756 Q96R06|SPAG5_HUMAN 378 382 PFstC 1757 Q96RG2|PASK_HUMAN 542 546 PFasC 1758 Q96RJ0|TAAR1_HUMAN 266 270 PFfiC 1759 Q96RQ9|OXLA_HUMAN 32 36 PFekC 1760 Q96SE7|ZN347_HUMAN 798 802 PFsiC 1761 Q96125|ZIC5_HUMAN 470 474 PFpgC 1762 Q99666|RGPD8_HUMAN 517 521 PFpvC 1763 Q99698|LYST_HUMAN 254 258 PFdlC 1764 Q99726|ZNT3_HUMAN 51 55 PFhhC 1765 Q9BSE5|SPEB_HUMAN 204 208 PFrrC 1766 Q9BWQ6|YIPF2_HUMAN 124 128 PFwiC 1767 Q9BXC9|BBS2_HUMAN 530 534 PFqvC 1768 Q9BXJ4|C1QT3_HUMAN 18 22 PFclC 1769 Q9BXK1|KLF16_HUMAN 130 134 PFpdC 1770 Q9BZE2|PUS3_HUMAN 261 265 PFqlC 1771 Q9C0C4|SEM4C_HUMAN 719 723 PFrpC 1772 Q9C0E2|XPO4_HUMAN 50 54 PFavC 1773 Q9C014|THS7B_HUMAN 1482 1486 PFsyC 1774 Q9GZN6|S6A16_HUMAN 271 275 PFflC 1775 Q9GZU2|PEG3_HUMAN 1330 1334 PFyeC 1776 Q9GZZ0|HXD1_HUMAN 162 166 PFpaC 1777 Q9H0A6|RNF32_HUMAN 344 348 PFhaC 1778 Q9H0B3|K1683_HUMAN 326 330 PFqiC 1779 Q9H267|VP33B_HUMAN 189 193 PFpnC 1780 Q9H2J1|CI037_HUMAN 102 106 PFekC 1781 Q9H3H5|GPT_HUMAN 77 81 PFInC 1782 Q9H8V3|ECT2_HUMAN 239 243 PFqdC 1783 Q9H9S0|NANOG_HUMAN 239 243 PFynC 1784 Q9H9V4|RN122_HUMAN 3 7 PFqwC 1785 Q9HAQ2|KIF9_HUMAN 291 295 PFrqC 1786 Q9HAW7|UD17_HUMAN 149 153 PFdaC 1787 Q9HAW8|UD110_HUMAN 149 153 PFdtC 1788 Q9HAW9|UD18_HUMAN 149 153 PFdaC 1789 Q9HBX8|LGR6_HUMAN 412 416 PFkpC 1790 Q9NQW8|CNGB3_HUMAN 309 313 PFdiC 1791 Q9NRZ9|HELLS_HUMAN 273 277 PFlvC 1792 Q9NTG7|SIRT3_HUMAN 30 34 PFgaC 1793 Q9NWZ5|UCKL1_HUMAN 370 374 PFqdC 1794 Q9NY30|BTG4_HUMAN 98 102 PFevC 1795 Q9NYM4|GPR83_HUMAN 342 346 PFiyC 1796 Q9NYV6|RRN3_HUMAN 561 565 PFdpC 1797 Q9NYW1|TA2R9_HUMAN 190 194 PFilC 1798 Q9NYW3|TA2R7_HUMAN 193 197 PFcvC 1799 Q9NZ56|FMN2_HUMAN 716 720 PFsdC 1800 Q9NZ71|RTEL1_HUMAN 495 499 PFpvC 1801 Q9NZD2|GLTP_HUMAN 31 35 PFfdC 1802 Q9P2N4|ATS9_HUMAN 596 600 PFgtC 1803 Q9UBR1|BUP1_HUMAN 124 128 PFafC 1804 Q9UBS0|KS6B2_HUMAN 344 348 PFrpC 1805 Q9UET6|RRMJ1_HUMAN 234 238 PFvtC 1806 Q9UHD4|CIDEB_HUMAN 37 41 PFrvC 1807 Q9UKA4|AKA11_HUMAN 917 921 PFshC 1808 Q9ULC3|RAB23_HUMAN 230 234 PFssC 1809 Q9ULJ3|ZN295_HUMAN 125 129 PFptC 1810 Q9ULK4|CRSP3_HUMAN 1086 1090 PFpnC 1811 Q9ULL4|PLXB3_HUMAN 24 28 PFglC 1812 Q9ULV8|CBLC_HUMAN 387 391 PFcrC 1813 Q9UM47|NOTC3_HUMAN 1357 1361 PFfrC 1814 Q9UNQ2|DIMT1_HUMAN 146 150 PFfrC 1815 Q9Y3D5|RT18C_HUMAN 86 90 PFtgC 1816 Q9Y3F1|TA6P_HUMAN 25 29 PFpsC 1817 Q9Y3R5|CU005_HUMAN 255 259 PFytC 1818 Q9Y450|HBS1L_HUMAN 487 491 PFrlC 1819 Q9Y493|ZAN_HUMAN 1364 1368 PFetC 1820 Q9Y493|ZAN_HUMAN 1751 1755 PFsqC 1821 Q9Y493|ZAN_HUMAN 2556 2560 PFaaC 1822 Q9Y548|YIPF1_HUMAN 123 127 PFwiC 1823 Q9Y5L3|ENP2_HUMAN 324 328 PFsrC 1824 Q9Y5P8|2ACC_HUMAN 272 276 PFqdC 1825 Q9Y664|KPTN_HUMAN 143 147 PFqlC 1826 Q9Y678|COPG_HUMAN 226 230 PFayC 1827 Q9Y6E0|STK24_HUMAN 371 375 PFsqC 1828 Q9Y6R7|FCGBP_HUMAN 683 687 PFavC 1829 Q9Y6R7|FCGBP_HUMAN 1074 1078 PFreC 1830 Q9Y6R7|FCGBP_HUMAN 1888 1892 PFttC 1831 Q9Y6R7|FCGBP_HUMAN 3089 3093 PFttC 1832 Q9Y6R7|FCGBP_HUMAN 4290 4294 PFttC 1833 Q9Y6R7|FCGBP_HUMAN 5059 5063 PFatC

TABLE 7A Table of the amino acid sequences of the peptides predicted similar to Growth Hormone Protein Name Peptide Location Peptide sequence SEQ ID NO: Placental Lactogen AAA98621(101-114) LLRISLLLIESWLE 2483 hGH-V AAB59548(101-114) LLRISLLLTQSWLE 2490 GH2 CAG46722(101-114) LLHISLLLIQSWLE 2491 Chorionic somatomammotropin AAA52116(101-113) LLRLLLLIESWLE 2480 Chorionic somatomammotropin AAI19748(12-25) LLHISLLLIESRLE 2482 hormone-like 1 Transmembrane protein 45A NP_060474(181-194) LLRSSLILLQGSWF 2481 IL-17 receptor C Q8NAC3(376-387) RLRLLTLQSWLL 2477 Neuropeptide FF receptor 2 Q9Y5X5(378-390) LLIVALLFILSWL 2479 Brush border myosin-I AAC27437(719-731) LMRKSQILISSWF 2478

TABLE 7B Table of the amino acid sequences of the peptides predicted similar to PEDF. SEQ Peptide ID Protein Name Peptide Location sequence NO: DEAH box AAH47327(438-448) EIELVEEEPPF 2485 polypeptide 8 (“DEAH” disclosed as SEQ ID NO: 2484) Caspase 10 CAD32371(67-77) AEDLLSEEDPF 2492 CKIP-1 CAI14263(66-76) TLDLIQEEDPS 2493

TABLE 8 Amino acid sequences of peptides that contain the somatotropin motif. Somatotropins Motif: L-X(3)-L-L-X(3)-S-X-L (SEQ ID NO: 2488) Number of Locations: 139 Number of Different Proteins: 139 SEQ Accession First Last ID Number|Protein Amino Amino NO: Name acid acid Sequence 1834 O14569|C56D2_HUMAN 164 175 LvgyLLgsaSlL 1835 O15287|FANCG_HUMAN 416 427 LceeLLsrtSsL 1836 O15482|TEX28_HUMAN 338 349 LatvLLvfvStL 1837 O43914|TYOBP_HUMAN 11 22 LllpLLlavSgL 1838 O60609|GFRA3_HUMAN 15 26 LmllLLlppSpL 1839 O75844|FACE1_HUMAN 279 290 LfdtLLeeySvL 1840 O95747|OXSR1_HUMAN 90 101 LvmkLLsggSvL 1841 P01241|SOMA_HUMAN 102 113 LrisLLliqSwL 1842 P01242|SOM2_HUMAN 102 113 LrisLLliqSwL 1843 P01243|CSH_HUMAN 102 113 LrisLLlieSwL 1844 P02750|A2GL_HUMAN 83 94 LpanLLggaSkL 1845 P03891|NU2M_HUMAN 149 160 LnvsLLltlSiL 1846 P04201|MAS_HUMAN 151 162 LvcaLLwalScL 1847 P05783|K1C18_HUMAN 338 349 LngiLLhleSeL 1848 P07359|GP1BA_HUMAN 3 14 LlllLLllpSpL 1849 P09848|LPH_HUMAN 35 46 LtndLLhnlSgL 1850 P11168|GTR2_HUMAN 136 147 LvgaLLmgfSkL 1851 P12034|FGF5_HUMAN 3 14 LsflLLlffShL 1852 P13489|RINI_HUMAN 247 258 LcpgLLhpsSrL 1853 P14902|I23O_HUMAN 196 207 LlkaLLeiaScL 1854 P16278|BGAL_HUMAN 135 146 LpawLLekeSiL 1855 P19838|NFKB1_HUMAN 558 569 LvrdLLevtSgL 1856 P22079|PERL_HUMAN 512 523 LvrgLLakkSkL 1857 P23276|KELL_HUMAN 53 64 LilgLLlcfSvL 1858 P24394|IL4RA_HUMAN 4 15 LcsgLLfpvScL 1859 P29320|EPHA3_HUMAN 5 16 LsilLLlscSvL 1860 P31512|FMO4_HUMAN 524 535 LaslLLickSsL 1861 P35270|SPRE_HUMAN 26 37 LlasLLspgSvL 1862 P41250|SYG_HUMAN 20 31 LpprLLarpSlL 1863 P42575|CASP2_HUMAN 114 125 LedmLLttlSgL 1864 P46721|SO1A2_HUMAN 396 407 LleyLLyfISfL 1865 P51665|PSD7_HUMAN 201 212 LnskLLdirSyL 1866 P59531|T2R12_HUMAN 188 199 LisfLLsliSlL 1867 P69849|NOMO3_HUMAN 1180 1191 LiplLLgltSrL 1868 P98161|PKID1_HUMAN 82 93 LdvgLLanlSaL 1869 P98171|RHG04_HUMAN 153 164 LqdeLLevvSeL 1870 P98196|AT11A_HUMAN 1077 1088 LaivLLytiSlL 1871 Q08431|MFGM_HUMAN 10 21 LcgaLLcapSlL 1872 Q08AF3|SLFN5_HUMAN 533 544 LvivLLgfkSfL 1873 Q12952|FOXL1_HUMAN 293 304 LgasLLaasSsL 1874 Q13275|SEM3F_HUMAN 2 13 LvagLLIwaSlL 1875 Q13394|MB211_HUMAN 300 311 LngiLLgliScL 1876 Q13609|DNSL3_HUMAN 8 19 LlllLLsihSaL 1877 Q13619|CUL4A_HUMAN 213 224 LlrsLLgmlSdL 1878 Q13620|CUL4B_HUMAN 349 360 LlrsLLsmlSdL 1879 Q14406|CSHL_HUMAN 84 95 LhisLLlieSrL 1880 Q14667|K0100_HUMAN 8 19 LlvlLLvalSaL 1881 Q15155|NOMO1_HUMAN 1180 1191 LiplLLgltSrL 1882 Q15760|GPR19_HUMAN 279 290 LilnLLfllSwL 1883 Q53RE8|ANR39_HUMAN 166 177 LacdLLpcnSdL 1884 Q5FWE3|PRRT3_HUMAN 586 597 LatdLLstwSvL 1885 Q5GH73|XKR6_HUMAN 630 641 LlyeLLgyeSsL 1886 Q5GH77|XKR3_HUMAN 194 205 LnraLLmtfSlL 1887 Q5JPE7|NOMO2_HUMAN 1180 1191 LiplLLgltSrL 1888 Q5JWR5|DOP1_HUMAN 506 517 LpqlLLrmiSaL 1889 Q5UIP0|RIF1_HUMAN 2413 2424 LsknLLagiSaL 1890 Q5VTE6|ANGE2_HUMAN 175 186 LsqdLLednShL 1891 Q5VU43|MYOME_HUMAN 1932 1943 LreaLLssrShL 1892 Q5VYK3|ECM29_HUMAN 1296 1307 LipaLLeslSvL 1893 Q68006|SLN13_HUMAN 554 565 LvivLLgfrSlL 1894 Q6GYQ0|GRIPE_HUMAN 641 652 LwddLLsvlSsL 1895 Q6NTF9|RHBD2_HUMAN 166 177 LvpwLLlgaSwL 1896 Q6ZMH5|S39A5_HUMAN 217 228 LavlLLslpSpL 1897 Q6ZMZ3|SYNE3_HUMAN 532 543 LhnsLLgrkSkL 1898 Q6ZVD8|PHLPL_HUMAN 313 324 LfpiLLceiStL 1899 Q6ZVE7|GOT1A_HUMAN 23 34 LfgtLLyfdSvL 1900 Q70J99|UN13D_HUMAN 927 938 LrveLLsasSlL 1901 Q7Z3Z4|PIWL4_HUMAN 139 150 LriaLLyshSeL 1902 Q7Z6Z7|HUWE1_HUMAN 841 852 LgegLLq1dSiL 1903 Q7Z7L1|SLN11_HUMAN 554 565 LvivLLgfrSlL 1904 Q86SM5|MRGRG_HUMAN 223 234 LlnfLLpvfSpL 1905 Q86U44|MTA70_HUMAN 78 89 LekkLLhhlSdL 1906 Q86UQ4|ABCAD_HUMAN 3182 3193 LlnsLLdivSsL 1907 Q86WI3|NLRC5_HUMAN 1485 1496 LlgsLLlslSeL 1908 Q86YC3|LRC33_HUMAN 263 274 LffpLLpgySkL 1909 Q8IYK4|GT252_HUMAN 9 20 LawsLLllsSaL 1910 Q8IYS0|GRM1C_HUMAN 485 496 LesdLLieeSvL 1911 Q8IZL8|PELP1_HUMAN 33 44 LrllLLesvSgL 1912 Q81ZY2|ABCA7_HUMAN 1746 1757 LftlLLqhrSqL 1913 Q8N0X7|SPG20_HUMAN 322 333 LfedLLrqmSdL 1914 Q8N6M3|CT142_HUMAN 33 44 LagsLLkelSpL 1915 Q8N816|TMM99_HUMAN 96 107 LlpcLLgvgSwL 1916 Q8NBM4|PDHL1_HUMAN 15 26 LsksLLlvpSaL 1917 Q8NCG7|DGLB_HUMAN 555 566 LtqpLLgegSlL 1918 Q8NFR9|I17RE_HUMAN 80 91 LcqhLLsggSgL 1919 Q8NGE3|O10P1_HUMAN 9 20 LpefLLlgfSdL 1920 Q8TCV5|WFDC5_HUMAN 8 19 LlgaLLavgSqL 1921 Q8TDL5|LPLC1_HUMAN 165 176 LriqLLhklSfL 1922 Q8TE82|S3TC1_HUMAN 1025 1036 LeggLLetiSqL 1923 Q8TEQ8|PIGO_HUMAN 857 868 LvflLLflgSfL 1924 Q8TEZ7|MPRB_HUMAN 127 138 LlahLLgskSeL 1925 Q8WWN8|CEND3_HUMAN 1481 1492 LeeqLLgelSsL 1926 Q8WZ84|OR8D1_HUMAN 43 54 LgmiLLiavSpL 1927 Q92535|PIGC_HUMAN 253 264 LfalLLmsiScL 1928 Q92538|GBF1_HUMAN 1224 1235 LrilLLmkpSvL 1929 Q92743|HTRA1_HUMAN 262 273 LpvlLLgrsSeL 1930 Q92935|EXTL1_HUMAN 19 30 LllvLLggfSlL 1931 Q93074|MED12_HUMAN 401 412 LgtiLLccpSaL 1932 Q96DN6|MBD6_HUMAN 740 751 LgasLLgdlSsL 1933 Q96GR4|ZDH12_HUMAN 48 59 LtflLLvlgSlL 1934 Q96HP8|T176A_HUMAN 29 40 LaklLLtccSaL 1935 Q96K12|FACR2_HUMAN 380 391 LmnrLLrtvSmL 1936 Q96KP1|EXOC2_HUMAN 339 350 LldkLLetpStL 1937 Q96MX0|CKLF3_HUMAN 40 51 LkgrLLlaeSgL 1938 Q96Q45|AL2S4_HUMAN 387 398 LvvaLLvglSwL 1939 Q96QZ0|PANX3_HUMAN 136 147 LssdLLfiiSeL 1940 Q96RQ9|OXLA_HUMAN 269 280 LpraLLsslSgL 1941 Q9BY08|EBPL_HUMAN 178 189 LipgLLlwqSwL 1942 Q9BZ97|TTY13_HUMAN 30 41 LclmLLlagScL 1943 Q9H1Y0|ATG5_HUMAN 85 96 LlfdLLassSaL 1944 Q9H254|SPTN4_HUMAN 1422 1433 LdkkLLhmeSqL 1945 Q9H330|CI005_HUMAN 430 441 LgkfLLkvdSkL 1946 Q9H418|SEHL2_HUMAN 175 186 LlqrLLksnShL 1947 Q9HCN3|TMEM8_HUMAN 200 211 LpqtLLshpSyL 1948 Q9NQ34|TMM9B_HUMAN 4 15 LwggLLrlgSlL 1949 Q9NR09|BIRC6_HUMAN 1400 1411 LlkaLLdnmSfL 1950 Q9NRA0|SPHK2_HUMAN 296 307 LgldLLlncSlL 1951 Q9NRU3|CNNM1_HUMAN 156 167 LgalLLlalSaL 1952 Q9NTT1|U2D3L_HUMAN 99 110 LskyLLsicSlL 1953 Q9NVH2|INT7_HUMAN 623 634 LridLLqafSqL 1954 Q9NVM9|CL011_HUMAN 350 361 LtnfUngrSvL 1955 Q9NZD1|GPC5D_HUMAN 60 71 LptqLLfllSvL 1956 Q9P2E9|RRBP1_HUMAN 1226 1237 LrglLLesqSqL 1957 Q9P2G4|K1383_HUMAN 397 408 LlnaLLvelSlL 1958 Q9P2V4|LRIT1_HUMAN 541 552 LpltLLvccSaL 1959 Q9UDY8|MALT1_HUMAN 33 44 LrepLLrrlSeL 1960 Q9UEW8|STK39_HUMAN 138 149 LvmkLLsggSmL 1961 Q9UGN4|CM35H_HUMAN 188 199 LlllLLvgaSlL 1962 Q9UHD4|CIDEB_HUMAN 189 200 LghmLLgisStL 1963 Q9U1G8|SO3A1_HUMAN 270 281 LcgaLLffsSlL 1964 Q9UPA5|BSN_HUMAN 353 364 LgasLLtgaStL 1965 Q9UPX8|SHAN2_HUMAN 609 620 LtgrLLdpsSpL 1966 Q9Y239|NOD1_HUMAN 318 329 LsgkLLkgaSkL 1967 Q9Y212|NTNG1_HUMAN 526 537 LlttLLgtaSpL 1968 Q9Y2U2|KCNK7_HUMAN 92 103 LpsaLLfaaSiL 1969 Q9Y2Y8|PRG3_HUMAN 7 18 LpflLLgtvSaL 1970 Q9Y586|MB212_HUMAN 300 311 LngiLLgliScL 1971 Q9Y5X0|SNX10_HUMAN 106 117 LqnaLLlsdSsL 1972 Q9Y5X5|NPFF2_HUMAN 379 390 LivaLLfilSwL

TABLE 9 Table of the amino acid sequences of the peptides identified to contain the serpin motif. Serpins Motif: L-X(2)-E-E-X-P (SEQ ID NO: 2489) Number of Locations: 314 Number of Different Proteins: 302 SEQ Accession First Last ID Number|Protein Amino Amino NO: Name acid acid Sequence 1973 O00160|MYO1F_HUMAN 744 751 LglEErPe 1974 O00507|USP9Y_HUMAN 2474 2481 LepEEePd 1975 O00625|PIR_HUMAN 134 141 LksEEiPk 1976 O14641|DVL2_HUMAN 20 27 LdeEEtPy 1977 O14686|MLL2_HUMAN 2819 2826 LgpEErPp 1978 O14709|ZN197_HUMAN 193 200 LsgEEnPr 1979 O14795|UN13B_HUMAN 1499 1506 LgnEEgPe 1980 O15013|ARHGA_HUMAN 199 206 LssEEpPt 1981 O15055|PER2_HUMAN 994 1001 LqlEEaPe 1982 O15528|CP27B_HUMAN 297 304 LfrEElPa 1983 O15534|PER1_HUMAN 987 994 LqlEElPr 1984 O43390|HNRPR_HUMAN 12 19 LkeEEePm 1985 O60216|RAD21_HUMAN 504 511 LppEEpPn 1986 O60237|MYPT2_HUMAN 339 346 LyeEEtPk 1987 O60346|PHLPP_HUMAN 483 490 LeaEEkPl 1988 O60779|S19A2_HUMAN 259 266 LnmEEpPv 1989 O60885|BRD4_HUMAN 913 920 LedEEpPa 1990 O75128|COBL_HUMAN 1064 1071 LerEEkPs 1991 O75420|PERQ1_HUMAN 334 341 LeeEEePs 1992 O75787|RENR_HUMAN 116 123 LfsEEtPv 1993 O75914|PAK3_HUMAN 5 12 LdnEEkPp 1994 O94933|SLIK3_HUMAN 227 234 LqlEEnPw 1995 O94966|UBP19_HUMAN 1251 1258 LeaEEePv 1996 O94986|CE152_HUMAN 847 854 LknEEvPv 1997 O94991|SLIK5_HUMAN 230 237 LqlEEnPw 1998 O95153|RIMB1_HUMAN 915 922 LngEEcPp 1999 O95279|KCNK5_HUMAN 443 450 LagEEsPq 2000 O95712|PA24B_HUMAN 772 779 LkiEEpPs 2001 O95881|TXD12_HUMAN 94 101 LedEEePk 2002 O96018|APBA3_HUMAN 116 123 LhcEEcPp 2003 O96024|B3GT4_HUMAN 217 224 LhsEEvPl 2004 P04275|VWF_HUMAN 1012 1019 LgvEEdPv 2005 P05160|F13B_HUMAN 18 25 LyaEEkPc 2006 P06858|LIPL_HUMAN 279 286 LlnEEnPs 2007 P07237|PDIA1_HUMAN 307 314 LkkEEcPa 2008 P07949|RET_HUMAN 1033 1040 LseEEtPl 2009 P08519|APOA_HUMAN 3880 3887 LpsEEaPt 2010 P09769|FGR_HUMAN 497 504 LdpEErPt 2011 P10745|IRBP_HUMAN 708 715 LwEEaPp 2012 P11532|DMD_HUMAN 2255 2262 LlvEElPl 2013 P14317|HCLS1_HUMAN 352 359 LgvEEePv 2014 P16150|LEUK_HUMAN 369 376 LkgEEePl 2015 P17025|ZN182_HUMAN 79 86 LevEEcPa 2016 P17600|SYN1_HUMAN 239 246 LgtEEfPl 2017 P18583|SON_HUMAN 1149 1156 LppEEpPt 2018 P18583|SON_HUMAN 1160 1167 LppEEpPm 2019 P18583|SON_HUMAN 1171 1178 LppEEpPe 2020 P19484|TFEB_HUMAN 350 357 LpsEEgPg 2021 P21333|FLNA_HUMAN 1034 1041 LprEEgPy 2022 P21802|FGFR2_HUMAN 33 40 LepEEpPt 2023 P22001|KCNA3_HUMAN 152 159 LreEErPl 2024 P31629|ZEP2_HUMAN 772 779 LvsEEsPs 2025 P34925|RYK_HUMAN 578 585 LdpEErPk 2026 P36955|PEDF_HUMAN 39 46 LveEEdPf 2027 P40189|IL6RB_HUMAN 787 794 LdsEErPe 2028 P42898|MTHR_HUMAN 598 605 LyeEEsPs 2029 P48729|KC1A_HUMAN 266 273 LrfEEaPd 2030 P51512|MMP16_HUMAN 165 172 LtfEEvPy 2031 P52746|ZN142_HUMAN 750 757 LgaEEnPl 2032 P53370|NUD16_HUMAN 284 291 LtvEElPa 2033 P53801|PTTG_HUMAN 167 174 LfkEEnPy 2034 P53804|TTC3_HUMAN 2001 2008 LltEEsPs 2035 P55285|CADH6_HUMAN 116 123 LdrEEkPv 2036 P55289|CAD12_HUMAN 117 124 LdrEEkPf 2037 P56645|PER3_HUMAN 929 936 LlgEEmPr 2038 P59797|SELV_HUMAN 163 170 LlpEEdPe 2039 Q01826|SATB1_HUMAN 409 416 LrkEEdPk 2040 Q04725|TLE2_HUMAN 200 207 LveEErPs 2041 Q06330|SUH_HUMAN 7 14 LpaEEpPa 2042 Q06889|EGR3_HUMAN 24 31 LypEEiPs 2043 Q07157|ZO1_HUMAN 1155 1162 LrhEEqPa 2044 Q13072|BAGE1_HUMAN 19 26 LmkEEsPv 2045 Q13087|PDIA2_HUMAN 497 504 LptEEpPe 2046 Q13255|GRM1_HUMAN 995 1002 LtaEEtPl 2047 Q13315|ATM_HUMAN 954 961 LpgEEyPl 2048 Q13439|GOGA4_HUMAN 2092 2099 LegEEnPg 2049 Q13596|SNX1_HUMAN 265 272 LekEElPr 2050 Q13634|CAD18_HUMAN 446 453 LdrEEtPw 2051 Q14028|CNGB1_HUMAN 137 144 LmaEEnPp 2052 Q14126|DSG2_HUMAN 117 124 LdrEEtPf 2053 Q14204|DYHC_HUMAN 3973 3980 LwsEEtPa 2054 Q14315|FLNC_HUMAN 1738 1745 LphEEePs 2055 Q14524|SCN5A_HUMAN 46 53 LpeEEaPr 2056 Q14554|PDIA5_HUMAN 166 173 LkkEEkPl 2057 Q14562|DHX8_HUMAN 411 418 LskEEfPd 2058 Q14562|DHX8_HUMAN 441 448 LveEEpPf 2059 Q14573|ITPR3_HUMAN 315 322 LaaEEnPs 2060 Q14674|ESPL1_HUMAN 613 620 LspEEtPa 2061 Q14676|MDC1_HUMAN 145 152 LtvEEtPr 2062 Q14684|RRP1B_HUMAN 244 251 LsaEEiPe 2063 Q15021|CND1_HUMAN 1179 1186 LgvEEePf 2064 Q15735|PI5PA_HUMAN 189 196 LasEEqPp 2065 Q15788|NCOA1_HUMAN 982 989 LimEErPn 2066 Q15878|CAC1E_HUMAN 797 804 LnrEEaPt 2067 Q2TAL6|VWC2_HUMAN 179 186 LctEEgPl 2068 Q32MZ4|LRRF1_HUMAN 82 89 LrvEErPe 2069 Q32P28|P3H1_HUMAN 215 222 LysEEqPq 2070 Q3KNS1|PTHD3_HUMAN 96 103 LpeEEtPe 2071 Q3ZCX4|ZN568_HUMAN 100 107 LegEEePw 2072 Q495W5|FUT11_HUMAN 144 151 LlhEEsPl 2073 Q52LD8|RFTN2_HUMAN 123 130 LviEEcPl 2074 Q53GL0|PKHO1_HUMAN 189 196 LigEEdPs 2075 Q53GL0|PKHO1_HUMAN 289 296 LraEEpPt 2076 Q53GL7|PAR10_HUMAN 693 700 LeaEEpPd 2077 Q53H47|SETMR_HUMAN 499 506 LdgEEaPk 2078 Q567U6|CCD93_HUMAN 300 307 LsaEEsPe 2079 Q580R0|CB027_HUMAN 41 48 LelEEaPe 2080 Q58719|SFT20_HUMAN 136 143 LrcEEaPs 2081 Q5H9T9|CN155_HUMAN 427 434 LlpEEaPr 2082 Q5H9T9|CN155_HUMAN 697 704 LpaEEtPi 2083 Q5H9T9|CN155_HUMAN 736 743 LltEEfPi 2084 Q5JUK9|GGED1_HUMAN 38 45 LqqEEpPi 2085 Q5JXB2|UE2NL_HUMAN 58 65 LlaEEyPm 2086 Q5MCW4|ZN569_HUMAN 60 67 LegEEePw 2087 Q5SYB0|FRPD1_HUMAN 553 560 LikEEqPp 2088 Q5THJ4|VP13D_HUMAN 2943 2950 LtgEEiPf 2089 Q5VYS4|CM033_HUMAN 293 300 LesEEtPn 2090 Q5VZP5|DUS27_HUMAN 942 949 LrlEEkPp 2091 Q5VZY2|PPC1A_HUMAN 247 254 LkkEErPt 2092 Q63HR2|TENC1_HUMAN 564 571 LddEEqPt 2093 Q66K74|MAP1S_HUMAN 777 784 LgaEEtPp 2094 Q68CZ1|FTM_HUMAN 1181 1188 LpaEEtPv 2095 Q68DD2|PA24F_HUMAN 470 477 LygEEnPa 2096 Q6BDS2|URFB1_HUMAN 1304 1311 LedEEiPv 2097 Q6DCA0|AMERL_HUMAN 183 190 LtrEElPk 2098 Q6DN90|IQEC1_HUMAN 263 270 LhtEEaPa 2099 Q6DT37|MRCKG_HUMAN 1264 1271 LypEElPp 2100 Q6HA08|ASTL_HUMAN 62 69 LilEEtPe 2101 Q6IFS5|HSN2_HUMAN 298 305 LngEElPp 2102 Q6NUN7|CK063_HUMAN 74 81 LdeEEsPr 2103 Q6P2Q9|PRP8_HUMAN 1852 1859 LpvEEqPk 2104 Q6P5W5|S39A4_HUMAN 473 480 LvaEEsPe 2105 Q6P6B1|CH047_HUMAN 249 256 LgkEEqPq 2106 Q6PD74|P34_HUMAN 141 148 LspEElPe 2107 Q6P148|SYDM_HUMAN 488 495 LpkEEnPr 2108 Q6PJ61|FBX46_HUMAN 246 253 LrkEErPg 2109 Q6S8J7|POTE8_HUMAN 307 314 LtsEEePq 2110 Q6SZW1|SARM1_HUMAN 396 403 LlgEEvPr 2111 Q6UX39|AMTN_HUMAN 114 121 LssEElPq 2112 Q6ZMY3|SPOC1_HUMAN 184 191 LskEEpPg 2113 Q6ZN11|ZN793_HUMAN 60 67 LegEEaPw 2114 Q6ZNL6|FGD5_HUMAN 382 389 LraEEnPm 2115 Q6ZV29|PLPL7_HUMAN 854 861 LhrEEgPa 2116 Q70CQ4|UBP31_HUMAN 527 534 LlNEEqPl 2117 Q70SY1|CR3L2_HUMAN 153 160 LekEEpPl 2118 Q7L8C5|SYT13_HUMAN 229 236 LasEEIPt 2119 Q7Z3E5|ARMC9_HUMAN 570 577 LnsEElPd 2120 Q7Z410|TMPS9_HUMAN 691 698 LacEEaPg 2121 Q86SP6|GP149_HUMAN 217 224 LcsEEpPr 2122 Q86V87|RAI16_HUMAN 496 503 LdlEEdPy 2123 Q86VQ0|CF152_HUMAN 428 435 LerEEkPe 2124 Q86W50|MET10_HUMAN 454 461 LsgEEnPe 2125 Q86Y13|DZIP3_HUMAN 1192 1199 LlpEEfPg 2126 Q86Y27|BAGE5_HUMAN 19 26 LmkEEsPv 2127 Q86Y28|BAGE4_HUMAN 19 26 LmkEEsPv 2128 Q86Y29|BAGE3_HUMAN 19 26 LmkEEsPv 2129 Q86Y30|BAGE2_HUMAN 19 26 LmkEEsPv 2130 Q8IU99|FA26C_HUMAN 315 322 LNEEpPl 2131 Q8IUA0|WFDC8_HUMAN 217 224 LqdEEcPl 2132 Q8IV63|VRK3_HUMAN 438 445 LtyEEkPp 2133 Q8IWY9|CDAN1_HUMAN 948 955 LlpEEtPa 2134 Q8IXI1|MIRO2_HUMAN 24 31 LvgEEfPe 2135 Q8IX12|MIRO1_HUMAN 24 31 LvsEEfPe 2136 Q8IYS5|OSCAR_HUMAN 122 129 LvtEEIPr 2137 Q81Z26|ZNF34_HUMAN 251 258 LhtEEkPy 2138 Q81ZH2|XRNl_HUMAN 1143 1150 LfdEEfPg 2139 Q8IZP0|ABI1_HUMAN 7 14 LleEEiPs 2140 Q8N201|INT1_HUMAN 1587 1594 LlgEEePl 2141 Q8N309|LRC43_HUMAN 373 380 LlvEEsPe 2142 Q8N3C0|HELC1_HUMAN 451 458 LsfEEkPv 2143 Q8N3C0|HELC1_HUMAN 1579 1586 LatEEdPk 2144 Q8N475|FSTL5_HUMAN 786 793 LkaEEwPw 2145 Q8N4L2|TM55A_HUMAN 132 139 LisEEqPa 2146 Q8N752|KC1AL_HUMAN 266 273 LrfEEvPd 2147 Q8NC74|CT151_HUMAN 178 185 LrgEEkPa 2148 Q8NE71|ABCF1_HUMAN 701 708 LrmEEtPt 2149 Q8NEG5|ZSWM2_HUMAN 43 50 LlrEEePe 2150 Q8NEM7|FA48A_HUMAN 115 122 LdaEElPp 2151 Q8NEZ4|MLL3_HUMAN 3046 3053 LllEEqPl 2152 Q8NEZ4|MLL3_HUMAN 4023 4030 LvkEEpPe 2153 Q8NFM7|I17RD_HUMAN 702 709 LgeEEpPa 2154 Q8NFP4|MDGA1_HUMAN 489 496 LplEEtPd 2155 Q8NHJ6|LIRB4_HUMAN 60 67 LdkEEsPa 2156 Q8N151|BORIS_HUMAN 120 127 LwlEEgPr 2157 Q8TBH0|ARRD2_HUMAN 387 394 LysEEdPn 2158 Q8TDX9|PK1L1_HUMAN 1101 1108 LsaEEsPg 2159 Q8TE68|ES8L1_HUMAN 408 415 LspEEgPp 2160 Q8TER0|SNED1_HUMAN 1083 1090 LrgEEhPt 2161 Q8WU49|CG033_HUMAN 8 15 LslEEcPw 2162 Q8WUA2|PPIL4_HUMAN 16 23 LytEErPr 2163 Q8WU14|HDAC7_HUMAN 943 950 LveEEePm 2164 Q8WWN8|CEND3_HUMAN 1456 1463 LNEErPp 2165 Q8WZ42|TITIN_HUMAN 12132 12139 LvvEElPv 2166 Q8WZ42|TITIN_HUMAN 13832 13839 LfvEEiPv 2167 Q92538|GBF1_HUMAN 1062 1069 LqrEEtPs 2168 Q92738|US6NL_HUMAN 51 58 LheEElPd 2169 Q92765|SFRP3_HUMAN 134 141 LacEElPv 2170 Q92851|CASPA_HUMAN 70 77 LlsEEdPf 2171 Q92888|ARHG1_HUMAN 390 397 LepEEpPg 2172 Q93008|USP9X_HUMAN 2466 2473 LcpEEePd 2173 Q969V6|MKL1_HUMAN 497 504 LvkEEgPr 2174 Q96B01|R51A1_HUMAN 55 62 LrkEEiPv 2175 Q96D15|RCN3_HUMAN 192 199 LhpEEfPh 2176 Q96DC7|TMC06_HUMAN 219 226 LqaEEaPe 2177 Q96FT7|ACCN4_HUMAN 90 97 LsIEEqPI 2178 Q96G97|BSCL2_HUMAN 326 333 LseEEkPd 2179 Q96GW7|PGCB_HUMAN 880 887 LhpEEdPe 2180 Q96H72|S39AD_HUMAN 340 347 LleEEdPw 2181 Q96H78|S2544_HUMAN 265 272 LmaEEgPw 2182 Q96J42|TXD15_HUMAN 42 49 LwsEEqPa 2183 Q96J17|SPTCS_HUMAN 1940 1947 LleEEaPd 2184 Q96JL9|ZN333_HUMAN 80 87 LkpEElPs 2185 Q96JQ0|PCD16_HUMAN 3106 3113 LyrEEgPp 2186 Q96MZ0|GD1L1_HUMAN 195 202 LdhEEePq 2187 Q96NZ9|PRAP1_HUMAN 71 78 LttEEkPr 2188 Q96PQ6|ZN317_HUMAN 109 116 LegEEePr 2189 Q96RE7|BTB14_HUMAN 133 140 LhaEEaPs 2190 Q96RG2|PASK_HUMAN 1196 1203 LvfEEnPf 2191 Q96RL1|UIMC1_HUMAN 388 395 LllEEePt 2192 Q96SB3|NEB2_HUMAN 435 442 LseEEdPa 2193 Q96SJ8|TSN18_HUMAN 167 174 LdsEEvPe 2194 Q99102|MUC4_HUMAN 1306 1313 LhrEErPn 2195 Q99543|DNJC2_HUMAN 68 75 LqlEEfPm 2196 Q9BQS2|SYT15_HUMAN 36 43 LtyEElPg 2197 Q9BVI0|PHF20_HUMAN 483 490 LepEEsPg 2198 Q9BY44|EIF2A_HUMAN 461 468 LheEEpPq 2199 Q9BY78|RNF26_HUMAN 356 363 LneEEpPg 2200 Q9BYD3|RM04_HUMAN 221 228 LthEEmPq 2201 Q9BZA7|PC11X_HUMAN 315 322 LdrEEtPn 2202 Q9BZA8|PC11Y_HUMAN 347 354 LdrEEtPn 2203 Q9C009|FOXQ1_HUMAN 227 234 LrpEEaPg 2204 Q9H095|IQCG_HUMAN 122 129 LitEEgPn 2205 Q9HOD2|ZN541_HUMAN 149 156 LggEEpPg 2206 Q9H2C0|GAN_HUMAN 36 43 LdgEEiPv 2207 Q9H2X9|S12A5_HUMAN 681 688 LrlEEgPp 2208 Q9H334|FOXP1_HUMAN 291 298 LshEEhPh 2209 Q9H3T3|SEM6B_HUMAN 26 33 LfpEEpPp 2210 Q9H579|CT132_HUMAN 138 145 LvqEErPh 2211 Q9H5V8|CDCP1_HUMAN 788 795 LatEEpPp 2212 Q9H6F5|CCD86_HUMAN 227 234 LnkEElPv 2213 Q9H6Z4|RANB3_HUMAN 4 11 LanEEkPa 2214 Q9H7E9|CH033_HUMAN 94 101 LapEEvPl 2215 Q9H8Y1|CN115_HUMAN 137 144 LcsEEsPe 2216 Q9H9E1|ANRA2_HUMAN 13 20 LivEEcPs 2217 Q9H9F9|ARP5_HUMAN 415 422 LfsEEtPg 2218 Q9HAV4|XPO5_HUMAN 521 528 LnrEEiPv 2219 Q9HCE7|SMUF1_HUMAN 364 371 LedEElPa 2220 Q9NPR2|SEM4B_HUMAN 47 54 LgsEErPf 2221 Q9NR50|EI2BG_HUMAN 333 340 LcpEEpPv 2222 Q9NRJ7|PCDBG_HUMAN 200 207 LdrEEePq 2223 Q9NTN9|SEM4G_HUMAN 203 210 LrlEEtPm 2224 Q9NUR3|CT046_HUMAN 104 111 LhsEEgPa 2225 Q9NVR7|TBCC1_HUMAN 138 145 LigEEwPs 2226 Q9NX46|ARHL2_HUMAN 235 242 LgmEErPy 2227 Q9NYB9|AB12_HUMAN 7 14 LleEEiPg 2228 Q9P1Y5|K1543_HUMAN 827 834 LlaEEtPp 2229 Q9P1Y5|K1543_HUMAN 938 945 LagEEaPg 2230 Q9P2E7|PCD10_HUMAN 316 323 LdyEEsPv 2231 Q9P2K9|PTHD2_HUMAN 673 680 LevEEePv 2232 Q9UBB4|ATX10_HUMAN 289 296 LasEEpPd 2233 Q9UBN6|TR10D_HUMAN 78 85 LkeEEcPa 2234 Q9UBT6|POLK_HUMAN 251 258 LlfEEsPs 2235 Q9UGF5|OR5U1_HUMAN 303 310 LskEElPq 2236 Q9UGL1|JAD1B_HUMAN 879 886 LlsEEtPs 2237 Q9UHW9|S12A6_HUMAN 743 750 LrlEEgPp 2238 Q9U1F9|BAZ2A_HUMAN 609 616 LsaEEiPs 2239 Q9UIG0|BAZ1B_HUMAN 75 82 LlkEEfPa 2240 Q9ULD6|PDZD6_HUMAN 390 397 LpaEEvPl 2241 Q9ULG1|INOC1_HUMAN 235 242 LssEEsPr 2242 Q9ULI4|K126A_HUMAN 1396 1403 LrgEEePr 2243 Q9ULQ1|TPC1_HUMAN 29 36 LNEElPs 2244 Q9UMS0|NFU1_HUMAN 93 100 LvtEEtPs 2245 Q9UN72|PCDA7_HUMAN 200 207 LdrEEtPe 2246 Q9UN73|PCDA6_HUMAN 200 207 LdrEEaPa 2247 Q9UN74|PCDA4_HUMAN 200 207 LdrEEaPe 2248 Q9UNA0|ATS5_HUMAN 481 488 LgpEElPg 2249 Q9UP95|S12A4_HUMAN 678 685 LrlEEgPp 2250 Q9UPQ7|PZRN3_HUMAN 385 392 LlpEEhPs 2251 Q9UPV0|CE164_HUMAN 488 495 LatEEePp 2252 Q9UPW6|SATB2_HUMAN 398 405 LrkEEdPr 2253 Q9UPW8|UN13A_HUMAN 332 339 LeeEElPe 2254 Q9UPX6|K1024_HUMAN 371 378 LntEEvPd 2255 Q9UQ05|KCNH4_HUMAN 761 768 LlgEElPp 2256 Q9UQ26|RIMS2_HUMAN 201 208 LrnEEaPq 2257 Q9UQ26|RIMS2_HUMAN 1327 1334 LsfEEsPq 2258 Q9Y250|LZTS1_HUMAN 293 300 LayEErPr 2259 Q9Y216|NLP_HUMAN 759 766 LelEEpPq 2260 Q9Y2K7|JHD1A_HUMAN 661 668 LlnEElPn 2261 Q9Y2L6|FRM4B_HUMAN 438 445 LpsEEdPa 2262 Q9Y2V3|RX_HUMAN 126 133 LseEEqPk 2263 Q9Y343|SNX24_HUMAN 87 94 LenEElPk 2264 Q9Y310|CV028_HUMAN 466 473 LvmEEaPe 2265 Q9Y3L3|3BP1_HUMAN 130 137 LseEElPa 2266 Q9Y3L3|3BP1_HUMAN 494 501 LasEElPs 2267 Q9Y3R5|DOP2_HUMAN 1084 1091 LseEElPy 2268 Q9Y426|CU025_HUMAN 98 105 LsfEEdPr 2269 Q9Y566|SHAN1_HUMAN 1838 1845 LpwEEgPg 2270 Q9Y572|RIPK3_HUMAN 352 359 LnlEEpPs 2271 Q9Y5E2|PCDB7_HUMAN 200 207 LdrEEiPe 2272 Q9Y5E3|PCDB6_HUMAN 199 206 LdrEEqPq 2273 Q9Y5E4|PCDB5_HUMAN 200 207 LdrEErPe 2274 Q9Y5E5|PCDB4_HUMAN 199 206 LdrEEqPe 2275 Q9Y5E6|PCDB3_HUMAN 200 207 LdrEEqPe 2276 Q9Y5E7|PCDB2_HUMAN 202 209 LdrEEqPe 2277 Q9Y5F1|PCDBC_HUMAN 200 207 LdyEErPe 2278 Q9Y5F2|PCDBB_HUMAN 200 207 LdyEElPe 2279 Q9Y5F3|PCDB1_HUMAN 200 207 LdrEEqPe 2280 Q9Y5G1|PCDGF_HUMAN 200 207 LdrEEqPh 2281 Q9Y5G2|PCDGE_HUMAN 410 417 LdrEEiPe 2282 Q9Y5H5|PCDA9_HUMAN 200 207 LdrEEtPe 2283 Q9Y512|PCDAA_HUMAN 199 206 LdrEEnPq 2284 Q9Y513|PCDA1_HUMAN 200 207 LdrEEtPe 2285 Q9Y5Q9|TF3C3_HUMAN 42 49 LsaEEnPd 2286 Q9Y5R2|MMP24_HUMAN 201 208 LtfEEvPy

TABLE 10 Table containing the amino acid sequence of the peptide predicted similar to Tumstatin/Tum4 Peptide Protein Name Location Peptide sequence Collagen type IV, CAI40758.1:  LPRFSTMPFIYCNINEVCHY alpha6 fibril 1630-1648 (SEQ ID NO: 2494)

In other embodiments, the following peptides suitable for use with the presently disclosed subject matter are disclosed in Table 1 of International PCT Patent Application Publication Number WO2007/033215 A2 for “Compositions Having Antiangiogenic Activity and Uses Thereof,” to Popel et al., published Mar. 22, 2007, which is incorporated herein by reference in its entirety.

TABLE 11 Anti-Angiogenic Peptide sequences SEQ ID NO:  Thrombospondin Containing Proteins 2287 ADAM-9 Q13443: 649-661 KCHGHGVCNSNKN 2288 ADAM-12 O43184: 662-675 MQCHGRGVCNNRKN 2289 ADAMTS-1 Q9UHI8: 566-584 GPWGDCSRTCGGGVQYTMR 2290 ADAMTS-2 CAA05880.1: 982-998 GPWSQCSVTCGNGTQER 2291 ADAMTS-3 NP_055058.1: 973-989 GPWSECSVTCGEGTEVR 2292 ADAMTS-4 CAH72146.1: 527-540 GPWGDCSRTCGGGV 2293 ADAMTS-4 CAH72146.1: 527-545 GPWGDCSRTCGGGVQFSSR 2294 ADAMTS-5 NP_008969.1: 882-898 GPWLACSRTCDTGWHTR 2295 ADAMTS-6 NP_922932.2: 847-860 QPWSECSATCAGGV 2296 ADAMTS-6 NP_922932.2: 847-863 QPWSECSATCAGGVQRQ 2297 ADAMTS-7 AAH61631.1: 1576-1592 GPWGQCSGPCGGGVQRR 2298 ADAMTS-7 AAH61631.1: 828-841 GPWTKCTVTCGRGV 2299 ADAMTS-8 Q9UP79: 534-547 GPWGECSRTCGGGV 2300 ADAMTS-8 Q9UP79: 534-552 GPWGECSRTCGGGVQFSHR 2301 ADAMTS-9 Q9P2N4: 1247-1261 WSSCSVTCGQGRATR 2302 ADAMTS-9 Q9P2N4: 1335-1351 GPWGACSSTCAGGSQRR 2303 ADAMTS-9 Q9P2N4: 595-613 SPFGTCSRTCGGGIKTAIR 2304 ADAMTS-10 Q9H324: 528-546 TPWGDCSRTCGGGVSSSSR 2305 ADAMTS-12 P58397: 1479-1493 WDLCSTSCGGGFQKR 2306 ADAMTS-12 P58397: 549-562 SPWSHCSRTCGAGV 2307 ADAMTS-13 AAQ88485.1: 751-765 WMECSVSCGDGIQRR 2308 ADAMTS-14 CAI13857.1: 980-994 WSQCSATCGEGIQQR 2309 ADAMTS-15 CAC86014.1: 900-916 SAWSPCSKSCGRGFQRR 2310 ADAMTS-16 Q8TE57: 1133-1149 SPWSQCTASCGGGVQTR 2311 ADAMTS-16 Q8TE57: 1133-1150 SPWSQCTASCGGGVQTRS 2312 ADAMTS-18 Q8TE60: 1131-1146 PWQQCTVTCGGGVQTR 2313 ADAMTS-18 Q8TE60: 1131-1147 PWQQCTVTCGGGVQTRS 2314 ADAMTS-18 Q8TE60: 998-1014 GPWSQCSKTCGRGVRKR 2315 ADAMTS-18 Q8TE60: 596-614 SKWSECSRTCGGGVKFQER 2316 ADAMTS-19 CAC84565.1: 1096-1111 WSKCSITCGKGMQSRV 2317 ADAMTS-20 CAD56159.3: 1478-1494 NSWNECSVTCGSGVQQR 2318 ADAMTS-20 CAD56159.3: 1309-1326 GPWGQCSSSCSGGLQHRA 2319 ADAMTS-20 CAD56159.3: 1661-1675 WSKCSVTCGIGIMKR 2320 ADAMTS-20 CAD56160.2: 564-581 PYSSCSRTCGGGIESATR 2321 BAI-1 O14514: 361-379 SPWSVCSSTCGEGWQTRTR 2322 BAI-2 O60241: 304-322 SPWSVCSLTCGQGLQVRTR 2323 BAI-3 CAI21673.1: 352-370 SPWSLCSFTCGRGQRTRTR 2324 C6 AAB59433.1: 30-48 TQWTSCSKTCNSGTQSRHR 2325 CILP AAQ89263.1 : 156-175 SPWSKCSAACGQTGVQTRTR 2326 CILP-2 AAN17826.1: 153 -171 GPWGPCSGSCGPGRRLRRR 2327 CTGF CAC44023.1 : 204-221 TEWSACSKTCGMGISTRV 2328 CYR61 AAR05446.1: 234-251 TSWSQCSKTCGTGISTRV 2329 Fibulin-6 CAC37630.1: 1574-1592 SAWRACSVTCGKGIQKRSR 2330 Fibulin-6 CAC37630.1 : 1688-1706 QPWGTCSESCGKGTQTRAR 2331 Fibulin-6 CAC37630.1 : 1745-1763 ASWSACSVSCGGGARQRTR 2332 NOVH AAL92490.1: 211-228 TEWTACSKSCGMGFSTRV 2333 Papilin NP_775733.2: 33-51 SQWSPCSRTCGGGVSFRER 2334 Papilin NP_775733.2: 342-359 GPWAPCSASCGGGSQSRS 2335 Properdin AAP43692.1: 143-161 GPWEPCSVTCSKGTRTRRR CYNSTGVDYRGTVSVTKSGRQCQPWNSQYPHTHTFTALRFPEL 2336 ROR-1 CAH71706.1: 313-391 NGGHSYCRNPGNQKEAPWCFTLDENFKSDLCDIPAC NHKCYNSTGVDYRGTVSVTKSGRQCQPWNSQYPHTHTFTALRF 2337 ROR-1 CAH71706.1: 310-391 PELNGGHSYCRNPGNQKEAPWCFTLDENFKSDLCDIPAC HKCYNSTGVDYRGTVSVTKSGRQCQPWNSQYPHTHTFTALRFP 2338 ROR-1 CAH71706.1: 311-388 ELNGGHSYCRNPGNQKEAPWCFTLDENFKSDLCDI HKCYNSTGVDYRGTVSVTKSGRQCQPWNSQYPHTHTFTALRFP 2339 ROR-1 CAH71706.1: 311-391 ELNGGHSYCRNPGNQKEAPWCFTLDENFKSDLCDIPAC KCYNSTGVDYRGTVSVTKSGRQCQPWNSQYPHTHTFTALRFPE 2340 ROR-1 CAH71706.1: 312-392 LNGGHSYCRNPGNQKEAPWCFTLDENFKSDLCDIPACD QCYNGSGMDYRGTASTTKSGHQCQPWALQHPHSHHLSSTDFPE 2341 ROR-2 Q01974: 315-395 LGGGHAYCRNPGGQMEGPWCFTQNKNVRMELCDVPSCS HQCYNGSGMDYRGTASTTKSGHQCQPWALQHPHSHHLSSTDFP 2342 ROR-2 Q01974: 314-391 ELGGGHAYCRNPGGQMEGPWCFTQNKNVRMELCDV HQCYNGSGMDYRGTASTTKSGHQCQPWALQHPHSHHLSSTDFP 2343 ROR-2 Q01974: 314-394 ELGGGHAYCRNPGGQMEGPWCFTQNKNVRMELCDVPSC HQCYNGSGMDYRGTASTTKSGHQCQPWALQHPHSHHLSSTDFP 2344 ROR-2 Q01974: 314-395 ELGGGHAYCRNPGGQMEGPWCFTQNKNVRMELCDVPSCS QCYNGSGMDYRGTASTTKSGHQCQPWALQHPHSHHLSSTDFPE 2345 ROR-2 Q01974: 315-394 LGGGHAYCRNPGGQMEGPWCFTQNKNVRMELCDVPSC 2346 Semaphorin 5A NP_003957.1: 660-678 GPWERCTAQCGGGIQARRR 2347 Semaphorin 5A NP_003957.1: 848-866 SPWTKCSATCGGGHYMRTR 2348 Semaphorin 5B AAQ88491.1: 916-934 TSWSPCSASCGGGHYQRTR 2349 SCO-spondin XP_379967.2: 3781-3799 GPWEDCSVSCGGGEQLRSR 2350 THSD1 AAQ88516.1: 347-365 QPWSQCSATCGDGVRERRR 2351 THSD3 AAH33140.1: 280-298 SPWSPCSGNCSTGKQQRTR 2352 THSD6 AAH40620.1: 44-60 WTRCSSSCGRGVSVRSR 2353 TSP-2 CAI23645.1: 444-462 SPWSSCSVTCGVGNITRIR 2354 TSP-2 CAI23645.1: 501-519 SPWSACTVTCAGGIRERTR 2355 TSRC1 AAH27478.1: 140-159 SPWSQCSVRCGRGQRSRQVR 2356 UNC5C AAH41156.1: 267-285 TEWSVCNSRCGRGYQKRTR 2357 UNC5D AAQ88514.1: 259-277 TEWSACNVRCGRGWQKRSR 2358 VSGP/F-spondin BAB18461.1: 567-583 WDECSATCGMGMKKRHR 2359 VSGP/F-spondin BAB18461.1: 621-639 SEWSDCSVTCGKGMRTRQR 2360 WISP-1 AAH74841.1: 221-238 SPWSPCSTSCGLGVSTRI 2361 WISP-2 AAQ89274.1: 199-216 TAWGPCSTTCGLGMATRV 2362 WISP-3 CAB16556.1: 191-208 TKWTPCSRTCGMGISNRV Collagens 2363 α1CIV CAH74130.1: 1479-1556 NERAHGQDLGTAGSCLRKFSTMPFLFCNINNVCNFASRNDYSY WLSTPEPMPMSMAPITGENIRPFISRCAVCEAPAM 2364 α1CIV CAH74130.1: 1494-1513 LRKFSTMPFLFCNINNVCNF 2365 α1CIV CAH74130.1: 1504-1523 FCNINNVCNFASRNDYSYWL 2366 α1CIV CAH74130.1: 1610-1628 SAPFIECHGRGTCNYYANA QEKAHNQDLGLAGSCLARFSTMPFLYCNPGDVCYYASRNDKSY 2367 α2CIV CAH71366.1: 1517-1593 WLSTTAPLPMMPVAEDEIKPYISRCSVCEAPAIA 2368 α2CIV CAH71366.1: 1542-1561 YCNPGDVCYYASRNDKSYWL 2369 α2CIV CAH71366.1: 1646-1664 ATPFIECNGGRGTCHYYAN QEKAHNQDLGLAGSCLPVFSTLPFAYCNIHQVCHYAQRNDRSY 2370 α4CIV CAA56943.1: 1499-1575 WLASAAPLPMMPLSEEAIRPYVSRCAVCEAPAQA 2371 α4CIV CAA56943.1: 1514-1533 LPVFSTLPFAYCNIHQVCHY 2372 α4CIV CAA56943.1: 1524-1543 YCNIHQVCHYAQRNDRSYWL 2373 α4CIV CAA56943.1: 1628-1646 AAPFLECQGRQGTCHFFAN NKRAHGQDLGTAGSCLRRFSTMPFMFCNINNVCNFASRNDYSY 2374 α5CIV AAC27816.1: 1495-1572 WLSTPEPMPMSMQPLKGQSIQPFISRCAVCEAPAV 2375 α5CIV AAC27816.1: 1510-1529 LRRFSTMPFMFCNINNVCNF 2376 α5CIV AAC27816.1: 1520-1539 FCNINNVCNFASRNDYSYWL 2377 α5CIV AAC27816.1: 1626-1644 SAPFIECHGRGTCNYYANS QEKAHNQDLGFAGSCLPRFSTMPFIYCNINEVCHYARRNDKSY 2378 α6CIV CAI40758.1: 1501-1577 WLSTTAPIPMMPVSQTQIPQYISRCSVCEAPSQA 2379 α6CIV CAI40758.1: 1526-1545 YCNINEVCHYARRNDKSYWL 2380 α6CIV CAI40758.1: 1630-1648 ATPFIECSGARGTCHYFAN CXC Chemokines 2381 ENA-78/CXCL5 AAP35453.1: 86-108 NGKEICLDPEAPFLKKVIQKILD RCVCLQTTQGVHPKMISNLQVFAIGPQCSKVEVVASLKNGKEIC 2382 ENA-78/CXCL5 AAP35453.1: 48-103 LDPEAPFLKKVI CLQTTQGVHPKMISNLQVFAIGPQCSKVEVVASLKNGKEICLDP 2383 ENA-78/CXCL5 AAP35453.1: 51-107 EAPFLKKVIQKIL 2384 GCP-2/CXCL6 AAH13744.1: 86-109 NGKQVCLDPEAPFLKKVIQKILDS LRCTCLRVTLRVNPKTIGKLQVFPAGPQCSKVEVVASLKNGKQV 2385 GCP-2/CXCL6 AAH13744.1: 47-106 CLDPEAPFLKKVIQKI RCTCLRVTLRVNPKTIGKLQVFPAGPQCSKVEVVASLKNGKQV 2386 GCP-2/CXCL6 AAH13744.1: 48-103 CLDPEAPFLKKVI CLRVTLRVNPKTIGKLQVFPAGPQCSKVEVVASLKNGKQVCLDP 2387 GCP-2/CXCL6 AAH13744.1: 51-107 EAPFLKKVIQKIL 2388 GRO-α/CXCL1 AAP35526.1: 80-103 NGRKACLNPASPIVKKIIEKMLNS RCQCLQTLQGIHPKNIQSVNVKSPGPHCAQTEVIATLKNGRKAC 2389 GRO-α/CXCL1 AAP35526.1: 42-97 LNPASPIVKKII QCLQTLQGIHPKNIQSVNVKSPGPHCAQTEVIATLKNGRKACLN 2390 GRO-α/CXCL1 AAP35526.1: 44-101 PASPIVKKIIEKML RCQCLQTLQGIHLKNIQSVKVKSPGPHCAQTEVIATLKNGQKAC 2391 Gro-β/CXCL2 AAH15753.1: 42-97 LNPASPMVKKII 2392 GRO-γ/MIP-2β/CXCL3 AAA63184.1: 79-100 NGKKACLNPASPMVQKIIEKIL QCLQTLQGIHLKNIQSVNVRSPGPHCAQTEVIATLKNGKKACLN 2393 GRO-γ/MIP-2β/CXCL3 AAA63184.1: 43-100 PASPMVQKIIEKIL RCQCLQTLQGIHLKNIQSVNVRSPGPHCAQTEVIATLKNGKKAC 2394 GRO-γ/MIP-2β/CXCL3 AAA63184.1: 41-96 LNPASPMVQKII QCIKTYSKPFHPKFIKELRVIESGPHCANTEIIVKLSDGRELCLDP 2395 IL-8/CXCL8 AAP35730.1: 35-94 KENWVQRVVEKFLK 2396 IL-8/CXCL8 AAP35730.1: 72-94 DGRELCLDPKENWVQRVVEKFLK RCTCISISNQPVNPRSLEKLEIIPASQFCPRVEIIATMKKKGEKRCL 2397 IP-10/CXCL10 AAH10954.1: 29-86 NPESKAIKNLL SCISTNQGTIHLQSLKDLKQFAPSPSCEKIEIIATLKNGVQTCLNP 2398 MIG/CXCL9 Q07325: 32-91 DSADVKELIKKWEK CVKTTSQVRPRHITSLEVIKAGPHCPTAQLIATLKNGRKICLDLQ 2399 PF-4/CXCL4 AAK29643.1: 43 -100 APLYKKIIKKLLE 2400 THBG-β/CXCL7 AAB46877.1: 100-121 DGRKICLDPDAPRIKKIVQKKL RCMCIKTTSGIHPKNIQSLEVIGKGTHCNQVEVIATLKDGRKICL 2401 THBG-β/CXCL7 AAB46877.1: 62-117 DPDAPRIKKIV MCIKTTSGIHPKNIQSLEVIGKGTHCNQVEVIATLKDGRKICLDP 2402 THBG-β/CXCL7 AAB46877.1: 64-121 DAPRIKKIVQKKL Kringle Containing Proteins 2403 AK-38 protein AAK74187.1: 14-93 DCMFGNGKGYRGKKATTVTGTPCQEWAAQEPHRHSTFIPGTNK WAGLEKNYCRNPDGDINGPWCYTMNPRKLFDYCDIPLCA 2404 AK-38 protein AAK74187.1: 12-94 QDCMFGNGKGYRGKKATTVTGTPCQEWAAQEPHRHSTFIPGTN KWAGLEKNYCRNPDGDINGPWCYTMNPRKLFDYCDIPLCA 2405 AK-38 protein AAK74187.1: 13-90 DCMFGNGKGYRGKKATTVTGTPCQEWAAQEPHRHSTFIPGTNK WAGLEKNYCRNPDGDINGPWCYTMNPRKLFDYCDI 2406 AK-38 protein AAK74187.1: 14-93 CMFGNGKGYRGKKATTVTGTPCQEWAAQEPHRHSTFIPGTNK WAGLEKNYCRNPDGDINGPWCYTMNPRKLFDYCDIPLC 2407 Hageman fct/cf XII AAM97932.1: 216-292 SCYDGRGLSYRGLARTTLSGAPCQPWASEATYRNVTAEQARN WGLGGHAFCRNPDNDIRPWCFVLNRDRLSWEYCDL 2408 Hageman fct/cf XII AAM97932.1: 214-295 KASCYDGRGLSYRGLARTTLSGAPCQPWASEATYRNVTAEQAR NWGLGGHAFCRNPDNDIRPWCFVLNRDRLSWEYCDLAQC 2409 Hageman fct/cf XII AAM97932.1: 215-296 ASCYDGRGLSYRGLARTTLSGAPCQPWASEATYRNVTAEQARN WGLGGHAFCRNPDNDIRPWCFVLNRDRLSWEYCDLAQCQ 2410 HGF P14210: 127-206 NCIIGKGRSYKGTVSITKSGIKCQPWSSMIPHEHSFLPSSYRGKDL QENYCRNPRGEEGGPWCFTSNPEVRYEVCDIPQC 2411 HGF P14210: 127-207 NCIIGKGRSYKGTVSITKSGIKCQPWSSMIPHEHSFLPSSYRGKDL QENYCRNPRGEEGGPWCFTSNPEVRYEVCDIPQCS 2412 HGF P14210: 304-377 ECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKC KDLRENYCRNPDGSESPWCFTTDPNIRVGYC 2413 HGF P14210: 210-289 ECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPD KGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCA 2414 HGF P14210: 304-383 ECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKC KDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNC 2415 Hyaluronan binding NP_004123.1: 192-277 DDCYVGDGYSYRGKMNRTVNQHACLYWNSHLLLQENYNMFM EDAETHGIGEHNFCRNPDADEKPWCFIKVTNDKVKWEYCDVSA CS 2416 Hyaluronan binding NP_004123.1: 192-276 DDCYVGDGYSYRGKMNRTVNQHACLYWNSHLLLQENYNMFM EDAETHGIGEHNFCRNPDADEKPWCFIKVTNDKVKWEYCDVSA C 2417 KREMEN-1 BAB40969.1: 31-114 ECFTANGADYRGTQNWTALQGGKPCLFWNETFQHPYNTLKYP NGEGGLGEHNYCRNPDGDVS- PWCYVAEHEDGVYWKYCEIPAC 2418 KREMEN-1 BAB40969.1: 31-115 ECFTANGADYRGTQNWTALQGGKPCLFWNETFQHPYNTLKYP NGEGGLGEHNYCRNPDGDVSPWCYVAEHEDGVYWKYCEIPAC Q 2419 KREMEN-2 BAD97142.1: 35-119 ECFQVNGADYRGHQNRTGPRGAGRPCLFWDQTQQHSYSSASDP HGRWGLGAHNFCRNPDGDVQ-PWCYVAETEEGIYWRYCDIPSC 2420 KREMEN-2 BAD97142.1: 34-119 SECFQVNGADYRGHQNRTGPRGAGRPCLFWDQTQQHSYSSASD PHGRWGLGAHNFCRNPDGDVQPWCYVAETEEGIYWRYCDIPSC 2421 Lp(a) NP_005568.1: 1615-1690 TEQRPGVQECYHGNGQSYRGTYSTTVTGRTCQAWSSMTPHSHS RTPEYYPNAGLIMNYCRNPDAVAAPYCYTRDPG 2422 Lp(a) NP_005568.1: 3560-3639 QDCYYHYGQSYRGTYSTTVTGRTCQAWSSMTPHQHSRTPENYP NAGLTRNYCRNPDAEIRPWCYTMDPSVRWEYCNLTQC 2423 Lp(a) NP_005568.1: 4123-4201 QCYHGNGQSYRGTFSTTVTGRTCQSWSSMTPHRHQRTPENYPN DGLTMNYCRNPDADTGPWCFTMDPSIRWEYCNLTRC 2424 Lp(a) NP_005568.1: 4225-4308 EQDCMFGNGKGYRGKKATTVTGTPCQEWAAQEPHRHSTFIPGT NKWAGLEKNYCRNPDGDINGPWCYTMNPRKLFDYCDIPLCA 2425 Macrophage stim. 1 AAH48330.1: 188-268 EAACVWCNGEEYRGAVDRTESGRECQRWDLQHPHQHPFEPGK FLDQGLDDNYCRNPDGSERPWCYTTDPQIEREFCDLPRC 2426 Macrophage stim. 1 AAH48330.1: 368-448 QDCYHGAGEQYRGTVSKTRKGVQCQRWSAETPHKPQFTFTSEP HAQLEENFCRNPDGDSHGPWCYTMDPRTPFDYCALRRC 2427 Macrophage stim. 1 AAH48330.1: 368-449 QDCYHGAGEQYRGTVSKTRKGVQCQRWSAETPHKPQFTFTSEP HAQLEENFCRNPDGDSHGPWCYTMDPRTPFDYCALRRCA 2428 Macrophage stim. 1 AAH48330.1: 370-448 CYHGAGEQYRGTVSKTRKGVQCQRWSAETPHKPQFTFTSEPHA QLEENFCRNPDGDSHGPWCYTMDPRTPFDYCALRRC 2429 Thrombin/cf II AAL77436.1: 105-186 EGNCAEGLGTNYRGHVNITRSGIECQLWRSRYPHKPEINSTTHP GADLQENFCRNPDSSTTGPWCYTTDPTVRRQECSIPVC 2430 Thrombin/cf II AAL77436.1: 106-186 GNCAEGLGTNYRGHVNITRSGIECQLWRSRYPHKPEINSTTHPG ADLQENFCRNPDSSTTGPWCYTTDPTVRRQECSIPVC 2431 Thrombin/cf II AAL77436.1: 107-183 NCAEGLGTNYRGHVNITRSGIECQLWRSRYPHKPEINSTTHPGA DLQENFCRNPDSSTTGPWCYTTDPTVRRQECSI 2432 Thrombin/cf II AAL77436.1: 107-186 NCAEGLGTNYRGHVNITRSGIECQLWRSRYPHKPEINSTTHPGA DLQENFCRNPDSSTTGPWCYTTDPTVRRQECSIPVC 2433 tPA AAH95403.1: 214-293 DCYFGNGSAYRGTHSLTESGASCLPWNSMILIGKVYTAQNPSAQ ALGLGKHNYCRNPDGDAKPWCHVLKSRRLTWEYCDV 2434 tPA AAH95403.1: 213-296 SDCYFGNGSAYRGTHSLTESGASCLPWNSMILIGKVYTAQNPSA QALGLGKHNYCRNPDGDAKPWCHVLKSRRLTWEYCDVPSC 2435 tPA AAH95403.1: 213-297 SDCYFGNGSAYRGTHSLTESGASCLPWNSMILIGKVYTAQNPSA QALGL GKHNYCRNPDGDAKPWCHVLKSRRLTWEYCDVPSCS 2436 tPA AAH95403.1: 214-296 DCYFGNGSAYRGTHSLTESGASCLPWNSMILIGKVYTAQNPSAQ ALGLGKHNYCRNPDGDAKPWCHVLKSRRLTWEYCDVPSC Somatotropins 2437 GH-1 NP_000506.2: 26-160 AFPTIPLSRLFDNAMLRAHRLHQLAFDTYQEFEEAYIPKEQKYSF LQNPQTSLCFSESIPTPSNREETQQKSNLELLRISLLLIQSWLEPVQ FLRSVFANSLVYGASDSNVYDLLKDLEEGIQTLMGRLEDGSPR 2438 GH-2 CAG46700.1: 26-160 AFPTIPLSRLFDNAMLRARRLYQLAYDTYQEFEEAYILKEQKYSF LQNPQTSLCFSESIPTPSNRAKTQQKSNLELLRISLLLIQSWLEPV QLLRSVFANSLVYGASDSNVYRHLKDLEEGIQTLMWRLEDGSP R 2439 Placental lactogen AAP35572.1: 26-160 AVQTVPLSRLFDHAMLQAHRAHQLAIDTYQEFEETYIPKDQKYS FLHDSQTSFCFSDSIPTPSNMEETQQKSNLELLRISLLLIESWLEPV RFLRSMFANNLVYDTSDSDDYHLLKDLEEGIQTLMGRLEDGSR R 2440 Somatoliberin AAH62475.1: 26-145 AFPTIPLSRLFDNASLRAHRLHQLAFDTYQEFNPQTSLCFSESIPT PSMREETQQKSNLELLRISLLLIQSWLEPVQFLRSVFANSLVYGA SDSNVYDLLKDLEEGIQTLMGRLEDGSPR TIMPs 2441 TIMP 3 AAA21815.1: 148-171 ECLWTDMLSNFGYPGYQSKHYACI 2442 TIMP 4 AAV38433.1: 175-198 ECLWTDWLLERKLYGYQAQHYVCM

In particular embodiments, the presently disclosed subject matter provides a nanoparticle, microparticle, or gel comprising a compound of Formula (I), wherein the one or more peptide is selected from the group consisting of an isolated peptide or analog thereof comprising the amino acid sequence W-X2-C-X3-C-X2-G, wherein X denotes a variable amino acid; W is tryptophan; C is cysteine, G is glycine; and

wherein the peptide reduces blood vessel formation in a cell, tissue or organ. In some embodiments, the one or more peptide is selected from the group consisting of an isolated peptide or analog thereof comprising or consisting essentially of a sequence having at least 85% amino acid sequence identity to an amino acid sequence selected from the group consisting of:

THSD-1: (SEQ ID NO: 2350) QPWSQCSATCGDGVRERRR; THSD-3: (SEQ ID NO: 2351) SPWSPCSGNCSTGKQQRTR; THSD-6: (SEQ ID NO: 2352) WTRCSSSCGRGVSVRSR; CILP: (SEQ ID NO: 2325) SPWSKCSAACGQTGVQTRTR; WISP-1: (SEQ ID NO: 2360) SPWSPCSTSCGLGVSTRI; WISP-2: (SEQ ID NO: 2361) TAWGPCSTTCGLGMATRV; WISP-3: (SEQ ID NO: 2362) TKWTPCSRTCGMGISNRV; F-spondin: (SEQ ID NO: 2359) SEWSDCSVTCGKGMRTRQR; F-spondin: (SEQ ID NO: 2358) WDECSATCGMGMKKRHR; CTGF: (SEQ ID NO: 2327) TEWSACSKTCGMGISTRV; fibulin-6: (SEQ ID NO: 2331) ASWSACSVSCGGGARQRTR; fibulin-6: (SEQ ID NO: 2330) QPWGTCSESCGKGTQTRAR; fibulin-6: (SEQ ID NO: 2329) SAWRACSVTCGKGIQKRSR; CYR61: (SEQ ID NO: 2328) TSWSQCSKTCGTGISTRV; NOVH: (SEQ ID NO: 2332) TEWTACSKSCGMGFSTRV; UNC5-C: (SEQ ID NO: 2356) TEWSVCNSRCGRGYQKRTR; UNC5-D: (SEQ ID NO: 2357) TEWSACNVRCGRGWQKRSR; SCO-spondin: (SEQ ID NO: 2349) GPWEDCSVSCGGGEQLRSR; Properdin: (SEQ ID NO: 2335) GPWEPCSVTCSKGTRTRRR; C6: (SEQ ID NO: 2324) TQWTSCSKTCNSGTQSRHR; ADAMTS-like-4: (SEQ ID NO: 2355) SPWSQCSVRCGRGQRSRQVR; ADAMTS-4: (SEQ ID NO: 2293) GPWGDCSRTCGGGVQFSSR; ADAMTS-8: (SEQ ID NO: 2300) GPWGECSRTCGGGVQFSHR; ADAMTS-16: (SEQ ID NO: 2310) SPWSQCTASCGGGVQTR; ADAMTS-18: (SEQ ID NO: 2315) SKWSECSRTCGGGVKFQER; semaphorin 5A: (SEQ ID NO: 2346) GPWERCTAQCGGGIQARRR; semaphorin 5A: (SEQ ID NO: 2347) SPWTKCSATCGGGHYMRTR; semaphoring 5B: (SEQ ID NO: 2348) TSWSPCSASCGGGHYQRTR; papilin: (SEQ ID NO: 2334) GPWAPCSASCGGGSQSRS; papilin: (SEQ ID NO: 2333) SQWSPCSRTCGGGVSFRER; ADAM-9: (SEQ ID NO: 2497) KCHGHGVCNS; and ADAM-12: (SEQ ID NO: 2288) MQCHGRGVCNNRKN,

wherein A is alanine; I is isoleucine; M is methionine; H is histidine; Y is tyrosine; K is lysine; W is tryptophan; C is cysteine, T is threonine, S is serine; N is asparagine; G is glycine; R is arginine; V is valine, P is proline, and Q is glutamine wherein the peptide reduces blood vessel formation in a cell, tissue or organ.

In other embodiments, the one or more peptide is selected from the group consisting of an isolated peptide or analog thereof having at least 85% identity to an amino acid sequence selected from the group consisting of:

ENA-78: (SEQ ID NO: 2381) NGKEICLDPEAPFLKKVIQKILD; CXCL6: (SEQ ID NO: 2384) NGKQVCLDPEAPFLKKVIQKILDS; CXCL1: (SEQ ID NO: 2388) NGRKACLNPASPIVKKIIEKMLNS; Gro-γ: (SEQ ID NO: 2392) NGKKACLNPASPMVQKIIEKIL; Beta thromboglobulin/CXCL7: (SEQ ID NO: 2400) DGRKICLDPDAPRIKKIVQKKL, Interleukin 8 (IL-8)/CXCL8: (SEQ ID NO: 2396) DGRELCLDPKENWVQRVVEKFLK, GCP-2: (SEQ ID NO: 2384) NGKQVCLDPEAPFLKKVIQKILDS,

wherein A is alanine; I is isoleucine; F is phenylalanine; D is aspartic acid; M is methionine; H is histidine; Y is tyrosine; K is lysine; W is tryptophan; C is cysteine, T is threonine, S is serine; N is asparagine; G is glycine; R is arginine; V is valine, P is proline, and Q is glutamine; and wherein the peptide reduces blood vessel formation in a cell, tissue or organ.

In yet other embodiments, the one or more peptide is selected from the group consisting of an isolated peptide or analog thereof having at least 85% amino acid sequence identity to an amino acid sequence selected from the group consisting of

Alpha 6 fibril of type 4 collagen: (SEQ ID NO: 2379) YCNINEVCHYARRNDKSYWL; Alpha 5 fibril of type 4 collagen: (SEQ ID NO: 2443) LRRFSTMPFMFCNINNVCNF; Alpha 4 fibril of type 4 collagen: (SEQ ID NO: 2373) AAPFLECQGRQGTCHFFAN; Alpha 4 fibril of type 4 collagen: (SEQ ID NO: 2371) LPVFSTLPFAYCNIHQVCHY; Alpha 4 fibril of type 4 collagen: (SEQ ID NO: 2372) YCNIHQVCHYAQRNDRSYVVL, and Collagen type IV, alpha6 fibril (SEQ ID NO: 2494) LPRFSTMPFIYCNINEVCHY;

wherein A is alanine; I is isoleucine; F is phenylalanine; D is aspartic acid; M is methionine; H is histidine; Y is tyrosine; K is lysine; W is tryptophan; C is cysteine, T is threonine, S is serine; N is asparagine; G is glycine; R is arginine; V is valine, P is proline, and Q is glutamine wherein the peptide reduces blood vessel formation in a cell, tissue or organ.

In other embodiments, peptides suitable for use in the presently disclosed subject matter are disclosed in U.S. Provisional Patent Application No. 61/421,706, filed Dec. 12, 2010, which is commonly owned, and is incorporated herein by reference in its entirety.

SEQ ID NO: ID Sequence 2443 SP2000 LRRFSTMPFMFCNINNVCNF 2444 SP2002 LRRFSTMPFMFGNINNVGNF 2445 SP2004 LRRFSTMPFMF 2446 SP2006 LRRFSTMPFMF-Abu-NINV 2447 SP2007 LRRFSTMPFMF-Abu 2448 SP2008 LRRFSTMP 2449 SP2009 NINNV-Abu-NF 2450 SP2010 FMF-Abu-NINNV-Abu-NF 2451 SP2011 STMPFMF-Abu-NINNV-Abu-NF 2452 SP2012 LRRFSTMPFMF-Abu-NINNV-Abu-NF 2453 SP2013 LNRFSTMPF 2454 SP2014 LRRFST-Nle-PF-Nle-F 2455 SP2015 LRRFSTMPAMF-Abu-NINNV-Abu-NF 2456 SP2016 LRRFSTMPFAF-Abu-NINNV-Abu-NF 2457 SP2017 LRRFSTMPFMA-Abu-NINNV-Abu-NF 2458 SP2018 LRRFSTMPF-Nle-F-Abu-NINNV-Abu-NF 2459 SP2019 LRRFSTMPFM(4-ClPhen)-Abu-CNINNV-Abu-NF 2460 SP2020 F-Abu-NINNV-Abu-N 2461 SP2021 F-Abu-NIN 2462 SP2022 LRRFSTMPFMFSNINNVSNF 2463 SP2023 LRRFSTMPFMFANINNVANF 2464 SP2024 LRRFSTMPFMFININNVINF 2465 SP2025 LRRFSTMPFMFTNINNVTNF 2466 SP2026 LRRFSTMPFMFC(AllyGly)NINNV(AllyGly)NF 2467 SP2027 LRRFSTMPFMFVNINNVVNF 2468 SP2028 LRRFSTMPFMF-Abu-NINN 2469 SP2029 LRRFSTMPFMFTNINV 2470 SP2030 F-Abu-NINV 2471 SP2031 FTNINNVTN 2472 SP2032 LRRFSTMPFMFTNINN 2473 SP2033 LRRFSTMPFMFININN 2474 SP2034 LRRFSTMPF-Da-FININNVINF 2475 SP2035 LRRFSTAPFAFININNVINF 2476 SP2036 LRRFSTMPFAFININNVINF; wherein Abu is 2-aminobutyric acid; Nle is Norleucine; and AllyGly is allyglycine.

In other embodiments, peptides suitable for use in the presently disclosed subject matter are disclosed in U.S. Provisional Patent Application No. 61/489,500, filed May 24, 2011, which also is commonly owned, and is incorporated herein by reference in its entirety.

SEQ ID NO: ID Sequence 2477 SP5001 RLRLLTLQSWLL 2478 SP5028 LMRKSQILISSWF 2479 SP5029 LLIVALLFILSWL 2480 SP5030 LLRLLLLIESWLE 2481 SP5031 LLRSSLILLQGSWF 2482 SP5032 LLHISLLLIESRLE 2483 SP5033 LLRISLLLIESWLE

III. Definitions

Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this presently described subject matter belongs.

While the following terms in relation to compounds of Formulae I-X are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to facilitate explanation of the presently disclosed subject matter. These definitions are intended to supplement and illustrate, not preclude, the definitions that would be apparent to one of ordinary skill in the art upon review of the present disclosure.

The terms substituted, whether preceded by the term “optionally” or not, and substituent, as used herein, refer to the ability, as appreciated by one skilled in this art, to change one functional group for another functional group provided that the valency of all atoms is maintained. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. The substituents also may be further substituted (e.g., an aryl group substituent may have another substituent off it, such as another aryl group, which is further substituted, for example, with fluorine at one or more positions).

When the term “independently selected” is used, the substituents being referred to (e.g., R groups, such as groups R₁, R₂, and the like, or variables, such as “m” and “n”), can be identical or different. For example, both R₁ and R₂ can be substituted alkyls, or R₁ can be hydrogen and R₂ can be a substituted alkyl, and the like.

A named “R” or group will generally have the structure that is recognized in the art as corresponding to a group having that name, unless specified otherwise herein. For the purposes of illustration, certain representative “R” groups as set forth above are defined below.

The term hydrocarbon, as used herein, refers to any chemical group comprising hydrogen and carbon. The hydrocarbon may be substituted or unsubstituted. As would be known to one skilled in this art, all valencies must be satisfied in making any substitutions. The hydrocarbon may be unsaturated, saturated, branched, unbranched, cyclic, polycyclic, or heterocyclic. Illustrative hydrocarbons are further defined herein below and include, for example, methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, allyl, vinyl, n-butyl, tert-butyl, ethynyl, cyclohexyl, methoxy, diethylamino, and the like.

As used herein the term “alkyl” refers to C₁₋₂₀ inclusive, linear (i.e., “straight-chain”), branched, or cyclic, saturated or at least partially and in some cases fully unsaturated (i.e., alkenyl and alkynyl) hydrocarbon radicals derived from a hydrocarbon moiety containing between one and twenty carbon atoms by removal of a single hydrogen atom. Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, iso-pentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, and the like, ethenyl, propenyl, butenyl, pentenyl, hexenyl, octenyl, butadienyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, and allenyl groups. “Branched” refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl or propyl, is attached to a linear alkyl chain. “Lower alkyl” refers to an alkyl group having 1 to about 8 carbon atoms (i.e., a C₁₋₈ alkyl), e.g., 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. “Higher alkyl” refers to an alkyl group having about 10 to about 20 carbon atoms, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. In certain embodiments, “alkyl” refers, in particular, to C₁₋₈ straight-chain alkyls. In other embodiments, “alkyl” refers, in particular, to C₁₋₈ branched-chain alkyls.

Alkyl groups can optionally be substituted (a “substituted alkyl”) with one or more alkyl group substituents, which can be the same or different. The term “alkyl group substituent” includes but is not limited to alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl. There can be optionally inserted along the alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, lower alkyl (also referred to herein as “alkylaminoalkyl”), or aryl.

Thus, as used herein, the term “substituted alkyl” includes alkyl groups, as defined herein, in which one or more atoms or functional groups of the alkyl group are replaced with another atom or functional group, including for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, and mercapto.

“Cyclic” and “cycloalkyl” refer to a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The cycloalkyl group can be optionally partially unsaturated. The cycloalkyl group also can be optionally substituted with an alkyl group substituent as defined herein, oxo, and/or alkylene. There can be optionally inserted along the cyclic alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl, thus providing a heterocyclic group. Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, and cycloheptyl. Multicyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, camphane, and noradamantyl.

The term “cycloalkylalkyl,” as used herein, refers to a cycloalkyl group as defined hereinabove, which is attached to the parent molecular moiety through an alkyl group, also as defined above. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.

The terms “cycloheteroalkyl” or “heterocycloalkyl” refer to a non-aromatic ring system, unsaturated or partially unsaturated ring system, such as a 3- to 10-member substituted or unsubstituted cycloalkyl ring system, including one or more heteroatoms, which can be the same or different, and are selected from the group consisting of N, O, and S, and optionally can include one or more double bonds. The cycloheteroalkyl ring can be optionally fused to or otherwise attached to other cycloheteroalkyl rings and/or non-aromatic hydrocarbon rings. Heterocyclic rings include those having from one to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. In certain embodiments, the term heterocylic refers to a non-aromatic 5-, 6-, or 7-membered ring or a polycyclic group wherein at least one ring atom is a heteroatom selected from O, S, and N (wherein the nitrogen and sulfur heteroatoms may be optionally oxidized), including, but not limited to, a bi- or tri-cyclic group, comprising fused six-membered rings having between one and three heteroatoms independently selected from the oxygen, sulfur, and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring. Representative cycloheteroalkyl ring systems include, but are not limited to pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadiazinanyl, tetrahydrofuranyl, and the like.

The term “alkenyl” as used herein refers to a monovalent group derived from a C₁₋₂₀ inclusive straight or branched hydrocarbon moiety having at least one carbon-carbon double bond by the removal of a single hydrogen atom. Alkenyl groups include, for example, ethenyl (i.e., vinyl), propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.

The term “cycloalkenyl” as used herein refers to a cyclic hydrocarbon containing at least one carbon-carbon double bond. Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3-cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl.

The term “alkynyl” as used herein refers to a monovalent group derived from a straight or branched C₁₋₂₀ hydrocarbon of a designed number of carbon atoms containing at least one carbon-carbon triple bond. Examples of “alkynyl” include ethynyl, 2-propynyl (propargyl), 1-propyne, 3-hexyne, and the like.

“Alkylene” refers to a straight or branched bivalent aliphatic hydrocarbon group having from 1 to about 20 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The alkylene group can be straight, branched or cyclic. The alkylene group also can be optionally unsaturated and/or substituted with one or more “alkyl group substituents.” There can be optionally inserted along the alkylene group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms (also referred to herein as “alkylaminoalkyl”), wherein the nitrogen substituent is alkyl as previously described. Exemplary alkylene groups include methylene (—CH₂—); ethylene (—CH₂—CH₂—); propylene (—(CH₂)₃—); cyclohexylene (—C₆H₁₀—); —CH═CH—CH═CH—; —CH═CH—CH₂—; —(CH₂)_(q)—N(R)—(CH₂)_(r)—, wherein each of q and r is independently an integer from 0 to about 20, e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and R is hydrogen or lower alkyl; methylenedioxyl (—O—CH₂—O—); and ethylenedioxyl (—O—(CH₂)₂—O—). An alkylene group can have about 2 to about 3 carbon atoms and can further have 6-20 carbons.

The term “aryl” is used herein to refer to an aromatic substituent that can be a single aromatic ring, or multiple aromatic rings that are fused together, linked covalently, or linked to a common group, such as, but not limited to, a methylene or ethylene moiety. The common linking group also can be a carbonyl, as in benzophenone, or oxygen, as in diphenylether, or nitrogen, as in diphenylamine. The term “aryl” specifically encompasses heterocyclic aromatic compounds. The aromatic ring(s) can comprise phenyl, naphthyl, biphenyl, diphenylether, diphenylamine and benzophenone, among others. In particular embodiments, the term “aryl” means a cyclic aromatic comprising about 5 to about 10 carbon atoms, e.g., 5, 6, 7, 8, 9, or 10 carbon atoms, and including 5- and 6-membered hydrocarbon and heterocyclic aromatic rings.

The aryl group can be optionally substituted (a “substituted aryl”) with one or more aryl group substituents, which can be the same or different, wherein “aryl group substituent” includes alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substituted aryl, aralkyl, hydroxyl, alkoxyl, aryloxyl, aralkyloxyl, carboxyl, acyl, halo, haloalkyl, nitro, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acyloxyl, amino, alkylamino, dialkylamino, trialkylamino, acylamino, aroylamino, carbamoyl, cyano, alkylcarbamoyl, dialkylcarbamoyl, carboxyaldehyde, carboxyl, alkoxycarbonyl, carboxamide, arylthio, alkylthio, alkylene, thioalkoxyl, and mercapto.

Thus, as used herein, the term “substituted aryl” includes aryl groups, as defined herein, in which one or more atoms or functional groups of the aryl group are replaced with another atom or functional group, including for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, and mercapto.

Specific examples of aryl groups include, but are not limited to, cyclopentadienyl, phenyl, furan, thiophene, pyrrole, pyran, pyridine, imidazole, benzimidazole, isothiazole, isoxazole, pyrazole, pyrazine, triazine, pyrimidine, quinoline, isoquinoline, indole, carbazole, and the like.

The terms “heteroaryl” and “aromatic heterocycle” and “aromatic heterocyclic” are used interchangeably herein and refer to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from sulfur, oxygen, and nitrogen; zero, one, or two ring atoms are additional heteroatoms independently selected from sulfur, oxygen, and nitrogen; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like. Aromatic heterocyclic groups can be unsubstituted or substituted with substituents selected from the group consisting of branched and unbranched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, trialkylamino, acylamino, cyano, hydroxy, halo, mercapto, nitro, carboxyaldehyde, carboxy, alkoxycarbonyl, and carboxamide. Specific heterocyclic and aromatic heterocyclic groups that may be included in the compounds of the invention include: 3-methyl-4-(3-methylphenyl)piperazine, 3 methylpiperidine, 4-(bis-(4-fluorophenyl)methyl)piperazine, 4-(diphenylmethyl)piperazine, 4(ethoxycarbonyl)piperazine, 4-(ethoxycarbonylmethyl)piperazine, 4-(phenylmethyl)piperazine, 4-(1-phenylethyl)piperazine, 4-(1,1-dimethylethoxycarbonyl)piperazine, 4-(2-(bis-(2-propenyl) amino)ethyl)piperazine, 4-(2-(diethylamino)ethyl)piperazine, 4-(2-chlorophenyl)piperazine, 4(2-cyanophenyl)piperazine, 4-(2-ethoxyphenyl)piperazine, 4-(2-ethylphenyl)piperazine, 4-(2-fluorophenyl)piperazine, 4-(2-hydroxyethyl)piperazine, 4-(2-methoxyethyl)piperazine, 4-(2-methoxyphenyl)piperazine, 4-(2-methylphenyl)piperazine, 4-(2-methylthiophenyl) piperazine, 4(2-nitrophenyl)piperazine, 4-(2-nitrophenyl)piperazine, 4-(2-phenylethyl)piperazine, 4-(2-pyridyl)piperazine, 4-(2-pyrimidinyl)piperazine, 4-(2,3-dimethylphenyl)piperazine, 4-(2,4-difluorophenyl) piperazine, 4-(2,4-dimethoxyphenyl)piperazine, 4-(2,4-dimethylphenyl)piperazine, 4-(2,5-dimethylphenyl)piperazine, 4-(2,6-dimethylphenyl)piperazine, 4-(3-chlorophenyl)piperazine, 4-(3-methylphenyl)piperazine, 4-(3-trifluoromethylphenyl)piperazine, 4-(3,4-dichlorophenyl)piperazine, 4-3,4-dimethoxyphenyl)piperazine, 4-(3,4-dimethylphenyl)piperazine, 4-(3,4-methylenedioxyphenyl)piperazine, 4-(3,4,5-trimethoxyphenyl)piperazine, 4-(3,5-dichlorophenyl)piperazine, 4-(3,5-dimethoxyphenyl)piperazine, 4-(4-(phenylmethoxy)phenyl)piperazine, 4-(4-(3,1-dimethylethyl)phenylmethyl)piperazine, 4-(4-chloro-3-trifluoromethylphenyl)piperazine, 4-(4-chlorophenyl)-3-methylpiperazine, 4-(4-chlorophenyl)piperazine, 4-(4-chlorophenyl)piperazine, 4-(4-chlorophenylmethyl)piperazine, 4-(4-fluorophenyl)piperazine, 4-(4-methoxyphenyl)piperazine, 4-(4-methylphenyl)piperazine, 4-(4-nitrophenyl)piperazine, 4-(4-trifluoromethylphenyl)piperazine, 4-cyclohexylpiperazine, 4-ethylpiperazine, 4-hydroxy-4-(4-chlorophenyl)methylpiperidine, 4-hydroxy-4-phenylpiperidine, 4-hydroxypyrrolidine, 4-methylpiperazine, 4-phenylpiperazine, 4-piperidinylpiperazine, 4-(2-furanyl)carbonyl)piperazine, 4-((1,3-dioxolan-5-yl)methyl)piperazine, 6-fluoro-1,2,3,4-tetrahydro-2-methylquinoline, 1,4-diazacylcloheptane, 2,3-dihydroindolyl, 3,3-dimethylpiperidine, 4,4-ethylenedioxypiperidine, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, azacyclooctane, decahydroquinoline, piperazine, piperidine, pyrrolidine, thiomorpholine, and triazole. The heteroaryl ring can be fused or otherwise attached to one or more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings, or heterocycloalkyl rings. A structure represented generally by the formula:

as used herein refers to a ring structure, for example, but not limited to a 3-carbon, a 4-carbon, a 5-carbon, a 6-carbon, a 7-carbon, and the like, aliphatic and/or aromatic cyclic compound, including a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure, comprising a substituent R group, wherein the R group can be present or absent, and when present, one or more R groups can each be substituted on one or more available carbon atoms of the ring structure. The presence or absence of the R group and number of R groups is determined by the value of the variable “n,” which is an integer generally having a value ranging from 0 to the number of carbon atoms on the ring available for substitution. Each R group, if more than one, is substituted on an available carbon of the ring structure rather than on another R group. For example, the structure above where n is 0 to 2 would comprise compound groups including, but not limited to:

and the like.

A dashed line representing a bond in a cyclic ring structure indicates that the bond can be either present or absent in the ring. That is, a dashed line representing a bond in a cyclic ring structure indicates that the ring structure is selected from the group consisting of a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure.

When a named atom of an aromatic ring or a heterocyclic aromatic ring is defined as being “absent,” the named atom is replaced by a direct bond.

As used herein, the term “acyl” refers to an organic acid group wherein the —OH of the carboxyl group has been replaced with another substituent and has the general formula RC(═O)—, wherein R is an alkyl, alkenyl, alkynyl, aryl, carbocylic, heterocyclic, or aromatic heterocyclic group as defined herein). As such, the term “acyl” specifically includes arylacyl groups, such as an acetylfuran and a phenacyl group. Specific examples of acyl groups include acetyl and benzoyl.

The terms “alkoxyl” or “alkoxy” are used interchangeably herein and refer to a saturated (i.e., alkyl-O—) or unsaturated (i.e., alkenyl-O— and alkynyl-O—) group attached to the parent molecular moiety through an oxygen atom, wherein the terms “alkyl,” “alkenyl,” and “alkynyl” are as previously described and can include C₁₋₂₀ inclusive, linear, branched, or cyclic, saturated or unsaturated oxo-hydrocarbon chains, including, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, n-butoxyl, sec-butoxyl, t-butoxyl, and n-pentoxyl, neopentoxy, n-hexoxy, and the like.

The term “alkoxyalkyl” as used herein refers to an alkyl-O-alkyl ether, for example, a methoxyethyl or an ethoxymethyl group.

“Aryloxyl” refers to an aryl-O— group wherein the aryl group is as previously described, including a substituted aryl. The term “aryloxyl” as used herein can refer to phenyloxyl or hexyloxyl, and alkyl, substituted alkyl, halo, or alkoxyl substituted phenyloxyl or hexyloxyl.

“Aralkyl” refers to an aryl-alkyl-group wherein aryl and alkyl are as previously described, and included substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.

“Aralkyloxyl” refers to an aralkyl-O— group wherein the aralkyl group is as previously described. An exemplary aralkyloxyl group is benzyloxyl.

“Alkoxycarbonyl” refers to an alkyl-O—CO— group. Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, and t-butyloxycarbonyl.

“Aryloxycarbonyl” refers to an aryl-O—CO— group. Exemplary aryloxycarbonyl groups include phenoxy- and naphthoxy-carbonyl.

“Aralkoxycarbonyl” refers to an aralkyl-O—CO— group. An exemplary aralkoxycarbonyl group is benzyloxycarbonyl.

“Carbamoyl” refers to an amide group of the formula —CONH₂. “Alkylcarbamoyl” refers to a R′RN—CO— group wherein one of R and R′ is hydrogen and the other of R and R′ is alkyl and/or substituted alkyl as previously described. “Dialkylcarbamoyl” refers to a R′RN—CO— group wherein each of R and R′ is independently alkyl and/or substituted alkyl as previously described.

The term carbonyldioxyl, as used herein, refers to a carbonate group of the formula —O—CO—OR.

“Acyloxyl” refers to an acyl-O— group wherein acyl is as previously described.

The term “amino” refers to the —NH₂ group and also refers to a nitrogen containing group as is known in the art derived from ammonia by the replacement of one or more hydrogen radicals by organic radicals. For example, the terms “acylamino” and “alkylamino” refer to specific N-substituted organic radicals with acyl and alkyl substituent groups respectively.

The terms alkylamino, dialkylamino, and trialkylamino as used herein refer to one, two, or three, respectively, alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom. The term alkylamino refers to a group having the structure —NHR′ wherein R′ is an alkyl group, as previously defined; whereas the term dialkylamino refers to a group having the structure —NR′R″, wherein R′ and R″ are each independently selected from the group consisting of alkyl groups. The term trialkylamino refers to a group having the structure —NR′R″R′″, wherein R′, R″, and R′″ are each independently selected from the group consisting of alkyl groups. Additionally, R′, R″, and/or R′″ taken together may optionally be —(CH₂)_(k)— where k is an integer from 2 to 6. Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, iso-propylamino, piperidino, trimethylamino, and propylamino.

The terms alkylthioether and thioalkoxyl refer to a saturated (i.e., alkyl-S—) or unsaturated (i.e., alkenyl-S— and alkynyl-S—) group attached to the parent molecular moiety through a sulfur atom. Examples of thioalkoxyl moieties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.

“Acylamino” refers to an acyl-NH— group wherein acyl is as previously described. “Aroylamino” refers to an aroyl-NH— group wherein aroyl is as previously described.

The term “carbonyl” refers to the —(C═O)— group.

The term “carboxyl” refers to the —COOH group. Such groups also are referred to herein as a “carboxylic acid” moiety.

The terms “halo,” “halide,” or “halogen” as used herein refer to fluoro, chloro, bromo, and iodo groups.

The term “hydroxyl” refers to the —OH group.

The term “hydroxyalkyl” refers to an alkyl group substituted with an —OH group.

The term “mercapto” refers to the —SH group.

The term “oxo” refers to a compound described previously herein wherein a carbon atom is replaced by an oxygen atom.

The term “nitro” refers to the —NO₂ group.

The term “thio” refers to a compound described previously herein wherein a carbon or oxygen atom is replaced by a sulfur atom.

The term “sulfate” refers to the —SO₄ group.

The term thiohydroxyl or thiol, as used herein, refers to a group of the formula —SH.

The term ureido refers to a urea group of the formula —NH—CO—NH₂.

Throughout the specification and claims, a given chemical formula or name shall encompass all tautomers, congeners, and optical- and stereoisomers, as well as racemic mixtures where such isomers and mixtures exist.

As used herein the term “monomer” refers to a molecule that can undergo polymerization, thereby contributing constitutional units to the essential structure of a macromolecule or polymer.

A “polymer” is a molecule of high relative molecule mass, the structure of which essentially comprises the multiple repetition of unit derived from molecules of low relative molecular mass, i.e., a monomer.

As used herein, an “oligomer” includes a few monomer units, for example, in contrast to a polymer that potentially can comprise an unlimited number of monomers. Dimers, trimers, and tetramers are non-limiting examples of oligomers.

Further, as used herein, the term “nanoparticle,” refers to a particle having at least one dimension in the range of about 1 nm to about 1000 nm, including any integer value between 1 nm and 1000 nm (including about 1, 2, 5, 10, 20, 50, 60, 70, 80, 90, 100, 200, 500, and 1000 nm and all integers and fractional integers in between). In some embodiments, the nanoparticle has at least one dimension, e.g., a diameter, of about 100 nm. In some embodiments, the nanoparticle has a diameter of about 200 nm. In other embodiments, the nanoparticle has a diameter of about 500 nm. In yet other embodiments, the nanoparticle has a diameter of about 1000 nm (1 μm). In such embodiments, the particle also can be referred to as a “microparticle. Thus, the term “microparticle” includes particles having at least one dimension in the range of about one micrometer (μm), i.e., 1×10⁻⁶ meters, to about 1000 μm. The term “particle” as used herein is meant to include nanoparticles and microparticles.

It will be appreciated by one of ordinary skill in the art that nanoparticles suitable for use with the presently disclosed methods can exist in a variety of shapes, including, but not limited to, spheroids, rods, disks, pyramids, cubes, cylinders, nanohelixes, nanosprings, nanorings, rod-shaped nanoparticles, arrow-shaped nanoparticles, teardrop-shaped nanoparticles, tetrapod-shaped nanoparticles, prism-shaped nanoparticles, and a plurality of other geometric and non-geometric shapes. In particular embodiments, the presently disclosed nanoparticles have a spherical shape.

The subject treated by the presently disclosed methods in their many embodiments is desirably a human subject, although it is to be understood that the methods described herein are effective with respect to all vertebrate species, which are intended to be included in the term “subject.” Accordingly, a “subject” can include a human subject for medical purposes, such as for the treatment of an existing condition or disease or the prophylactic treatment for preventing the onset of a condition or disease, or an animal subject for medical, veterinary purposes, or developmental purposes. Suitable animal subjects include mammals including, but not limited to, primates, e.g., humans, monkeys, apes, and the like; bovines, e.g., cattle, oxen, and the like; ovines, e.g., sheep and the like; caprines, e.g., goats and the like; porcines, e.g., pigs, hogs, and the like; equines, e.g., horses, donkeys, zebras, and the like; felines, including wild and domestic cats; canines, including dogs; lagomorphs, including rabbits, hares, and the like; and rodents, including mice, rats, and the like. An animal may be a transgenic animal. In some embodiments, the subject is a human including, but not limited to, fetal, neonatal, infant, juvenile, and adult subjects. Further, a “subject” can include a patient afflicted with or suspected of being afflicted with a condition or disease. Thus, the terms “subject” and “patient” are used interchangeably herein.

“Associated with”: When two entities are “associated with” one another as described herein, they are linked by a direct or indirect covalent or non-covalent interaction. Preferably, the association is covalent. Desirable non-covalent interactions include hydrogen bonding, van der Waals interactions, hydrophobic interactions, magnetic interactions, electrostatic interactions, etc.

“Biocompatible”: The term “biocompatible”, as used herein is intended to describe compounds that are not toxic to cells. Compounds are “biocompatible” if their addition to cells in vitro results in less than or equal to 20% cell death, and their administration in vivo does not induce inflammation or other such adverse effects.

“Biodegradable”: As used herein, “biodegradable” compounds are those that, when introduced into cells, are broken down by the cellular machinery or by hydrolysis into components that the cells can either reuse or dispose of without significant toxic effect on the cells (i.e., fewer than about 20% of the cells are killed when the components are added to cells in vitro). The components preferably do not induce inflammation or other adverse effects in vivo. In certain preferred embodiments, the chemical reactions relied upon to break down the biodegradable compounds are uncatalyzed.

“Effective amount”: In general, the “effective amount” of an active agent or drug delivery device refers to the amount necessary to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of an agent or device may vary depending on such factors as the desired biological endpoint, the agent to be delivered, the composition of the encapsulating matrix, the target tissue, and the like.

“Peptide” or “protein”: A “peptide” or “protein” comprises a string of at least three amino acids linked together by peptide bonds. The terms “protein” and “peptide” may be used interchangeably. Peptide may refer to an individual peptide or a collection of peptides. Inventive peptides preferably contain only natural amino acids, although non-natural amino acids (i.e., compounds that do not occur in nature but that can be incorporated into a polypeptide chain) and/or amino acid analogs as are known in the art may alternatively be employed. Also, one or more of the amino acids in an inventive peptide may be modified, for example, by the addition of a chemical entity such as a carbohydrate group, a phosphate group, a famesyl group, an isofarnesyl group, a fatty acid group, a linker for conjugation, functionalization, or other modification, etc. In a preferred embodiment, the modifications of the peptide lead to a more stable peptide (e.g., greater half-life in vivo). These modifications may include cyclization of the peptide, the incorporation of D-amino acids, etc. None of the modifications should substantially interfere with the desired biological activity of the peptide.

“Polynucleotide” or “oligonucleotide”: Polynucleotide or oligonucleotide refers to a polymer of nucleotides. Typically, a polynucleotide comprises at least three nucleotides. The polymer may include natural nucleosides (i.e., adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxyguanosine, and deoxycytidine), nucleoside analogs (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, C5-propynylcytidine, C5-propynyluridine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-methylcytidine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, 0(6)-methylguanine, and 2-thiocytidine), chemically modified bases, biologically modified bases (e.g., methylated bases), intercalated bases, modified sugars (e.g., 2′-fluororibose, ribose, 2′-deoxyribose, arabinose, and hexose), or modified phosphate groups (e.g., phosphorothioates and 5′-N-phosphoramidite linkages).

“Small molecule”: As used herein, the term “small molecule” refers to organic compounds, whether naturally-occurring or artificially created (e.g., via chemical synthesis) that have relatively low molecular weight and that are not proteins, polypeptides, or nucleic acids. Typically, small molecules have a molecular weight of less than about 1500 g/mol. Also, small molecules typically have multiple carbon-carbon bonds. Known naturally-occurring small molecules include, but are not limited to, penicillin, erythromycin, taxol, cyclosporin, and rapamycin. Known synthetic small molecules include, but are not limited to, ampicillin, methicillin, sulfamethoxazole, and sulfonamides.

By “analog” is meant a chemical compounds having a structure that is different from the general structure of a reference agent, but that functions in a manner similar to the reference agent. For example, a peptide analog having a variation in sequence or having a modified amino acid.

By “thrombospondin (TSP) derived peptide” is meant a peptide comprising a TSP motif: W-X(2)-C-X(3)-C-X(2)-G (SEQ ID NO: 2486). Exemplary TSP derived peptides are shown in Tables 1 and 2. If desired, the peptide includes at least about 5, 10, 20, 30, 40, 50 or more amino acids that flank the carboxy or amino terminus of the motif in the naturally occurring amino acid sequence of the peptide. TSP1 derived peptides include, for example, those derived from proteins WISP-1 (SPWSPCSTSCGLGVSTRI; SEQ ID NO: 2360), NOVH (TEWTACSKSCGMGFSTRV; SEQ ID NO: 2332) and UNC5C (TEWSVCNSRCGRGYQKRTR; SEQ ID NO: 2456).

By “CXC derived peptide” is meant a peptide comprising a CXC Motif: G-X(3)-C-L. Exemplary CXC derived peptides are shown in Table 3. If desired, the peptide includes at least about 5, 10, 20, 30, 40, 50 or more amino acids that flank the carboxy or amino terminus of the motif in the naturally occurring amino acid sequence. CXC derived peptides include, for example, those derived from proteins GRO-u/CXCL1 (NGRKACLNPASPIVKKIIEKMLNS (SEQ ID NO: 2388)), GRO-y/MIP-20/CXCL3 (NGKKACLNPASPMVQKIIEKIL (SEQ ID NO: 2392)), and ENA-78/CXCL5 (NGKEICLDPEAPFLKKVIQKILD (SEQ ID NO: 2381)).

By “Collagen IV derived peptide” is meant a peptide comprising a C-N-X(3)-V-C (SEQ ID NO: 2487) or P—F-X(2)-C collagen motif Exemplary collagen IV derived peptides are shown in Table 5. If desired, the peptide includes at least about 5, 10, 20, 30, 40, 50 or more amino acids that flank the carboxy or amino terminus of the motif in the naturally occurring amino acid sequence. Type IV collagen derived peptides include, for example, LRRFSTMPFMFCNINNVCNF (SEQ ID NO: 2375) and FCNINNVCNFASRNDYSYWL (SEQ ID NO: 2365), and LPRFSTMPFIYCNINEVCHY (SEQ ID NO: 2494).

By “Somatotropin derived peptide” is meant a peptide comprising a Somatotropin Motif: L-X(3)-L-L-X(3)-S-X-L (SEQ ID NO: 2488). Exemplary somatotropin derived peptides are shown in Table 8. If desired, the peptide includes at least about 5, 10, 20, 30, 40, 50 or more amino acids that flank the carboxy or amino terminus of the motif in the naturally occurring amino acid sequence.

By “Serpin derived peptide” is meant a peptide comprising a Serpin Motif: L-X(2)-E-E-X-P (SEQ ID NO: 2489). Exemplary serpin derived peptides are shown in Table 9. If desired, the peptide includes at least about 5, 10, 20, 30, 40, 50 or more amino acids that flank the carboxy or amino terminus of the motif in the naturally occurring amino acid sequence.

By “Beta 1 integrin” is meant a polypeptide that binds a collagen IV derived peptide or that has at least about 85% identity to NP_596867 or a fragment thereof.

By “Beta 3 integrin” is meant a polypeptide that binds a collagen IV derived peptide or that has at least about 85% identity to P05106 or a fragment thereof.

By “CD36” is meant a CD36 glycoprotein that binds to a thrombospondin-derived peptide or that has at least about 85% identity to NP_001001548 or a fragment thereof. CD36 is described, for example, by Oquendo et al., “CD36 directly mediates cytoadherence of Plasmodium falciparum parasitized erythrocytes,” Cell 58: 95-101, 1989.

By “CD47” is meant a CD47 glycoprotein that binds to a thrombospondin-derived peptides or that has at least about 85% identity to NP_000315 or a fragment thereof. CD47 is described, for example, by Han et al., “CD47, a ligand for the macrophage fusion receptor, participates in macrophage multinucleation.” J. Biol. Chem. 275: 37984-37992, 2000.

By “CXCR3” is meant a G protein coupled receptor or fragment thereof having at least about 85% identity to NP_001495. CXCR3 is described, for example, by Trentin et al., “The chemokine receptor CXCR3 is expressed on malignant B cells and mediates chemotaxis.” J. Clin. Invest. 104: 115-121, 1999.

By “blood vessel formation” is meant the dynamic process that includes one or more steps of blood vessel development and/or maturation, such as angiogenesis, vasculogenesis, formation of an immature blood vessel network, blood vessel remodeling, blood vessel stabilization, blood vessel maturation, blood vessel differentiation, or establishment of a functional blood vessel network.

By “angiogenesis” is meant the growth of new blood vessels originating from existing blood vessels. Angiogenesis can be assayed by measuring the total length of blood vessel segments per unit area, the functional vascular density (total length of perfused blood vessel per unit area), or the vessel volume density (total of blood vessel volume per unit volume of tissue).

By “vasculogenesis” is meant the development of new blood vessels originating from stem cells, angioblasts, or other precursor cells.

By “blood vessel stability” is meant the maintenance of a blood vessel network.

By “alteration” is meant a change in the sequence or in a modification (e.g., a post-translational modification) of a gene or polypeptide relative to an endogeneous wild-type reference sequence.

By “ameliorate” is meant decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease.

By “antibody” is meant any immunoglobulin polypeptide, or fragment thereof, having immunogen binding ability.

In this disclosure, “comprises,” “comprising,” “containing” and “having” and the like can have the meaning ascribed to them in U.S. Patent law and can mean “includes,” “including,” and the like; “consisting essentially of” or “consists essentially” likewise has the meaning ascribed in U.S. Patent law and the term is open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art embodiments.

A “cancer” in an animal refers to the presence of cells possessing characteristics typical of cancer-causing cells, for example, uncontrolled proliferation, loss of specialized functions, immortality, significant metastatic potential, significant increase in anti-apoptotic activity, rapid growth and proliferation rate, and certain characteristic morphology and cellular markers. In some circumstances, cancer cells will be in the form of a tumor; such cells may exist locally within an animal, or circulate in the blood stream as independent cells, for example, leukemic cells.

By “disease” is meant any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.

By “fragment” is meant a portion of a polypeptide or nucleic acid molecule. This portion contains, preferably, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the entire length of the reference nucleic acid molecule or polypeptide. A fragment may contain 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 nucleotides or amino acids.

By “isolated nucleic acid molecule” is meant a nucleic acid (e.g., a DNA) that is free of the genes, which, in the naturally occurring genome of the organism from which the nucleic acid molecule of the invention is derived, flank the gene. The term therefore includes, for example, a recombinant DNA that is incorporated into a vector; into an autonomously replicating plasmid or virus; or into the genomic DNA of a prokaryote or eukaryote; or that exists as a separate molecule (for example, a cDNA or a genomic or cDNA fragment produced by PCR or restriction endonuclease digestion) independent of other sequences. In addition, the term includes an RNA molecule which is transcribed from a DNA molecule, as well as a recombinant DNA which is part of a hybrid gene encoding additional polypeptide sequence.

By an “isolated polypeptide” is meant a polypeptide of the invention that has been separated from components that naturally accompany it. Typically, the polypeptide is isolated when it is at least 60%, by weight, free from the proteins and naturally-occurring organic molecules with which it is naturally associated. Preferably, the preparation is at least 75%, more preferably at least 90%, and most preferably at least 99%, by weight, a polypeptide of the invention. An isolated polypeptide of the invention may be obtained, for example, by extraction from a natural source, by expression of a recombinant nucleic acid encoding such a polypeptide; or by chemically synthesizing the protein. Purity can be measured by any appropriate method, for example, column chromatography, polyacrylamide gel electrophoresis, or by HPLC analysis.

By “marker” is meant any protein or polynucleotide having an alteration in expression level or activity that is associated with a disease or disorder.

“By “neoplasia” is meant a disease that is caused by or results in inappropriately high levels of cell division, inappropriately low levels of apoptosis, or both. Solid tumors, hematological disorders, and cancers are examples of neoplasias.

By “operably linked” is meant that a first polynucleotide is positioned adjacent to a second polynucleotide that directs transcription of the first polynucleotide when appropriate molecules (e.g., transcriptional activator proteins) are bound to the second polynucleotide.

By “peptide” is meant any fragment of a polypeptide. Typically peptide lengths vary between 5 and 1000 amino acids (e.g., 5, 10, 15, 20, 25, 50, 100, 200, 250, 500, 750, and 1000).

By “polypeptide” is meant any chain of amino acids, regardless of length or post-translational modification.

By “promoter” is meant a polynucleotide sufficient to direct transcription.

By “reduce” is meant a decrease in a parameter (e.g., blood vessel formation) as detected by standard art known methods, such as those described herein. As used herein, reduce includes a 10% change, preferably a 25% change, more preferably a 40% change, and even more preferably a 50% or greater change.

By “reference” is meant a standard or control condition.

By “substantially identical” is meant a polypeptide or nucleic acid molecule exhibiting at least 50% identity to a reference amino acid sequence (for example, any one of the amino acid sequences described herein) or nucleic acid sequence (for example, any one of the nucleic acid sequences described herein). Preferably, such a sequence is at least 60%, more preferably 80% or 85%, and even more preferably 90%, 95% or even 99% identical at the amino acid level or nucleic acid to the sequence used for comparison.

Sequence identity is typically measured using sequence analysis software (for example, Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, Wis. 53705, BLAST, BESTFIT, GAP, or PILEUP/PRETTYBOX programs). Such software matches identical or similar sequences by assigning degrees of homology to various substitutions, deletions, and/or other modifications. Conservative substitutions typically include substitutions within the following groups: glycine, alanine; valine, isoleucine, leucine; aspartic acid, glutamic acid, asparagine, glutamine; serine, threonine; lysine, arginine; and phenylalanine, tyrosine. In an exemplary approach to determining the degree of identity, a BLAST program may be used, with a probability score between e⁻³ and e⁻¹⁰⁰ indicating a closely related sequence.

“Sequence identity” or “identity” in the context of two nucleic acid or polypeptide sequences includes reference to the residues in the two sequences which are the same when aligned for maximum correspondence over a specified comparison window, and can take into consideration additions, deletions and substitutions. When percentage of sequence identity is used in reference to proteins it is recognized that residue positions which are not identical often differ by conservative amino acid substitutions, where amino acid residues are substituted for other amino acid residues with similar chemical properties (for example, charge or hydrophobicity) and therefore do not deleteriously change the functional properties of the molecule. Where sequences differ in conservative substitutions, the percent sequence identity may be adjusted upwards to correct for the conservative nature of the substitution. Sequences which differ by such conservative substitutions are said to have sequence similarity. Approaches for making this adjustment are well-known to those of skill in the art. Typically this involves scoring a conservative substitution as a partial rather than a full mismatch, thereby increasing the percentage sequence identity. Thus, for example, where an identical amino acid is given a score of 1 and a non-conservative substitution is given a score of zero, a conservative substitution is given a score between zero and 1. The scoring of conservative substitutions is calculated, for example, according to the algorithm of Meyers and Miller, Computer Applic. Biol. Sci., 4: 11-17, 1988, for example, as implemented in the program PC/GENE (Intelligenetics, Mountain View, Calif., USA).

“Percentage of sequence identity” means the value determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the polynucleotide sequence in the comparison window may comprise additions, substitutions, or deletions (i.e., gaps) as compared to the reference sequence (which does not comprise additions, substitutions, or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity.

The term “substantial identity” or “homologous” in their various grammatical forms in the context of polynucleotides means that a polynucleotide comprises a sequence that has a desired identity, for example, at least 60% identity, preferably at least 70% sequence identity, more preferably at least 80%, still more preferably at least 90% and even more preferably at least 95%, compared to a reference sequence using one of the alignment programs described using standard parameters. One of skill will recognize that these values can be appropriately adjusted to determine corresponding identity of proteins encoded by two nucleotide sequences by taking into account codon degeneracy, amino acid similarity, reading frame positioning and the like. Substantial identity of amino acid sequences for these purposes normally means sequence identity of at least 60%, more preferably at least 70%, 80%, 85%, 90%, and even more preferably at least 95%.

Another indication that nucleotide sequences are substantially identical is if two molecules hybridize to each other under stringent conditions. However, nucleic acids which do not hybridize to each other under stringent conditions are still substantially identical if the polypeptides which they encode are substantially identical. This may occur, for example, when a copy of a nucleic acid is created using the maximum codon degeneracy permitted by the genetic code. One indication that two nucleic acid sequences are substantially identical is that the polypeptide which the first nucleic acid encodes is immunologically cross reactive with the polypeptide encoded by the second nucleic acid, although such cross-reactivity is not required for two polypeptides to be deemed substantially identical.

An “expression vector” is a nucleic acid construct, generated recombinantly or synthetically, bearing a series of specified nucleic acid elements that enable transcription of a particular gene in a host cell. Typically, gene expression is placed under the control of certain regulatory elements, including constitutive or inducible promoters, tissue-preferred regulatory elements, and enhancers.

A “recombinant host” may be any prokaryotic or eukaryotic cell that contains either a cloning vector or expression vector. This term also includes those prokaryotic or eukaryotic cells that have been genetically engineered to contain the cloned gene(s) in the chromosome or genome of the host cell.

The term “operably linked” is used to describe the connection between regulatory elements and a gene or its coding region. That is, gene expression is typically placed under the control of certain regulatory elements, including constitutive or inducible promoters, tissue-specific regulatory elements, and enhancers. Such a gene or coding region is said to be “operably linked to” or “operatively linked to” or “operably associated with” the regulatory elements, meaning that the gene or coding region is controlled or influenced by the regulatory element.

A “reference sequence” is a defined sequence used as a basis for sequence comparison. A reference sequence may be a subset of or the entirety of a specified sequence; for example, a segment of a full-length cDNA or gene sequence, or the complete cDNA or gene sequence. For polypeptides, the length of the reference polypeptide sequence will generally be at least about 5, 10, or 15 amino acids, preferably at least about 20 amino acids, more preferably at least about 25 amino acids, and even more preferably about 35 amino acids, about 50 amino acids, about 100 amino acids, or about 150 amino acids. For nucleic acids, the length of the reference nucleic acid sequence will generally be at least about 50 nucleotides, preferably at least about 60 nucleotides, more preferably at least about 75 nucleotides, and even more preferably about 100 nucleotides about 300 nucleotides or about 450 nucleotides or any integer thereabout or therebetween.

Methods of alignment of sequences for comparison are well-known in the art. Optimal alignment of sequences for comparison may be conducted by the local homology algorithm of Smith and Waterman, Adv. Appl. Math., 2: 482, 1981; by the homology alignment algorithm of Needleman and Wunsch, J Mol. Biol., 48: 443, 1970; by the search for similarity method of Pearson and Lipman, Proc. Natl. Acad. Sci. USA, 8: 2444, 1988; by computerized implementations of these algorithms, including, but not limited to: CLUSTAL in the PC/Gene program by Intelligenetics, Mountain View, Calif., GAP, BESTFIT, BLAST, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group (GCG), 7 Science Dr., Madison, Wis., USA; the CLUSTAL program is well described by Higgins and Sharp, Gene, 73: 237-244, 1988; Corpet, et al., Nucleic Acids Research, 16:10881-10890, 1988; Huang, et al., Computer Applications in the Biosciences, 8:1-6, 1992; and Pearson, et al., Methods in Molecular Biology, 24:7-331, 1994. The BLAST family of programs which can be used for database similarity searches includes: BLASTN for nucleotide query sequences against nucleotide database sequences; BLASTX for nucleotide query sequences against protein database sequences; BLASTP for protein query sequences against protein database sequences; TBLASTN for protein query sequences against nucleotide database sequences; and TBLASTX for nucleotide query sequences against nucleotide database sequences. See, Current Protocols in Molecular Biology, Chapter 19, Ausubel, et al., Eds., Greene Publishing and Wiley-Interscience, New York, 1995. New versions of the above programs or new programs altogether will undoubtedly become available in the future, and can be used with the present invention.

Unless otherwise stated, sequence identity/similarity values provided herein refer to the value obtained using the BLAST 2.0 suite of programs, or their successors, using default parameters (Altschul et al., Nucleic Acids Res, 2:3389-3402, 1997). It is to be understood that default settings of these parameters can be readily changed as needed in the future.

As those ordinary skilled in the art will understand, BLAST searches assume that proteins can be modeled as random sequences. However, many real proteins comprise regions of nonrandom sequences which may be homopolymeric tracts, short-period repeats, or regions enriched in one or more amino acids. Such low-complexity regions may be aligned between unrelated proteins even though other regions of the protein are entirely dissimilar. A number of low-complexity filter programs can be employed to reduce such low-complexity alignments. For example, the SEG (Wooten and Federhen, Comput. Chem., 17:149-163, 1993) and XNU (Clayerie and States, Comput. Chem., 17:191-1, 1993) low-complexity filters can be employed alone or in combination.

As used herein, the terms “treat,” “treating,” “treatment,” and the like refer to reducing or ameliorating a disorder and/or symptoms associated therewith. It will be appreciated that, although not precluded, treating a disorder or condition does not require that the disorder, condition or symptoms associated therewith be completely eliminated.

A “tumor,” as used herein, refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues.

As used herein, the terms “prevent,” “preventing,” “prevention,” “prophylactic treatment” and the like refer to reducing the probability of developing a disorder or condition in a subject, who does not have, but is at risk of or susceptible to developing a disorder or condition.

Following long-standing patent law convention, the terms “a,” “an,” and “the” refer to “one or more” when used in this application, including the claims. Thus, for example, reference to “a subject” includes a plurality of subjects, unless the context clearly is to the contrary (e.g., a plurality of subjects), and so forth.

Throughout this specification and the claims, the terms “comprise,” “comprises,” and “comprising” are used in a non-exclusive sense, except where the context requires otherwise. Likewise, the term “include” and its grammatical variants are intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that can be substituted or added to the listed items.

For the purposes of this specification and appended claims, unless otherwise indicated, all numbers expressing amounts, sizes, dimensions, proportions, shapes, formulations, parameters, percentages, parameters, quantities, characteristics, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term “about” even though the term “about” may not expressly appear with the value, amount or range. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are not and need not be exact, but may be approximate and/or larger or smaller as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art depending on the desired properties sought to be obtained by the presently disclosed subject matter. For example, the term “about,” when referring to a value can be meant to encompass variations of, in some embodiments, ±100% in some embodiments ±50%, in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from the specified amount, as such variations are appropriate to perform the disclosed methods or employ the disclosed compositions.

Further, the term “about” when used in connection with one or more numbers or numerical ranges, should be understood to refer to all such numbers, including all numbers in a range and modifies that range by extending the boundaries above and below the numerical values set forth. The recitation of numerical ranges by endpoints includes all numbers, e.g., whole integers, including fractions thereof, subsumed within that range (for example, the recitation of 1 to 5 includes 1, 2, 3, 4, and 5, as well as fractions thereof, e.g., 1.5, 2.25, 3.75, 4.1, and the like) and any range within that range.

EXAMPLES

The following Examples have been included to provide guidance to one of ordinary skill in the art for practicing representative embodiments of the presently disclosed subject matter. In light of the present disclosure and the general level of skill in the art, those of skill can appreciate that the following Examples are intended to be exemplary only and that numerous changes, modifications, and alterations can be employed without departing from the scope of the presently disclosed subject matter. The following Examples are offered by way of illustration and not by way of limitation.

Example 1 Methods Synthesis of BR6

All chemicals were purchased from Sigma-Aldrich Chemical Co. (St. Louis, Mo., USA) and used without further purification. Bis(2-hydroxyethyl) disulfide (15.4 g, 10 mmol) and triethylamine (TEA, 37.5 mL, 300 mmol) were dissolved in 450 mL of tetrahydrofuran previously dried with NaSO₄ in a 1000 ml round bottom flask. The flask was flushed with N2 for 10 min and then maintained under a N2 environment. Acryloyl chloride (24.4 mL, 300 mmol) was dissolved in 50 mL tetrahydrofuran then added to the flask dropwise over 2 hrs while stirring. The reaction was carried out for 24 hrs, then the TEA HCl precipitate was removed by filtration, and the solvent was removed by rotary evaporation. The product was dissolved in 100 mL dichloromethane and washed five times with 200 mL of an aqueous solution of 0.2 M Na₂CO₃ and three times with distilled water. The solution was dried with NaSO₄ and the solvent was removed by rotary evaporation.

Polymer Synthesis

Base monomer BR6 was polymerized with side chain monomers S3, S4, and S5 at a base:side chain ratio of 1.2:1 by weight without solvent at 90° C. for 24 hrs while stirring. For end-capping with E10, base polymer was dissolved in anhydrous dimethyl sulfoxide at 100 mg/mL with 0.2 mM end-cap. The reaction was allowed to proceed for 1 hr at room temperature while shaking.

Example 2 Characteristics of Representative Polymer/Peptide Nanoparticles

Referring now to FIG. 5 are shown representative formation and sizing of polymer/peptide nanoparticles (by nanoparticle tracking analysis on a Nanosight LM10). Selected peptides and PBAEs were diluted in 25 mM sodium acetate buffer and then together in different weight-to-weight ratios. In some embodiments w/w is unity, 1:1, in other embodiments there is an excess of polymer to peptide. In some embodiments this ratio is 5:1, in other embodiments between 1:1-10:1, in other embodiments it is 10:1 to 20:1. In FIG. 6, both a 5:1 and 1:1 ratio is shown. The mixtures were incubated at room temperature for up to 10 minutes to allow for self-assembly and then loaded into the NanoSight laser cell. Using NanoSight nanoparticle tracking software and analysis, individual particles were tracked in order to determine the average size distribution of the particles. In the case of more hydrophilic peptides (DEAH Box poly8; “DEAH” disclosed as SEQ ID NO: 2484) and PBAEs (336), there were very few background particles, that is very few particles of peptide or PBAE only. However, when self-assembled, a noticeable nanoparticle distribution was observed, with an average size ranging from 100-150 nm. In the case of hydrophobic peptides and PBAEs, they have the possibility of aggregating with themselves. In the case of the peptide-PBAE mixture, a shift in the mean can be observed as a way to detect difference in nanoparticle formation.

Referring now to FIG. 6, is shown DEAH peptide (SEQ ID NO: 2484) release by 336 nanoparticles at 4° C. (above) and 37° C. (below). Changing polymer to peptide formulation ratios and concentrations are key to tune release. Slowing the reaction rate of degradation of the liable polymer bonds extends release from nanoparticles. This is shown by change in temperature, but could also be accomplished by increasing hydrophobicity of the polymer, increasing the molecular weight between liable ester groups, or other modifications known by someone in the art; FITC labeled DEAH peptide (SEQ ID NO: 2484) and 336 polymer were mixed and incubated for up to 10 minutes in sodium acetate buffer. Mixtures at different peptide concentrations, but constant polymer to peptide ratios, as well as peptide only were added to a 96-well plate. Fluorescence measurements were obtained using a plate reader and measured over time. The plates were kept either at 4° C. or 37° C.

Referring now to FIG. 7, is shown HUVEC viability/proliferation assays with polymer/SP6001/DEAH peptide (“DEAH” disclosed as SEQ ID NO: 2484); the CellTiter 96® AQueous One Solution Cell Proliferation assay was used to see the effect of both peptide and polymer on cell proliferation and viability. Polymers at the right concentrations have minimal cytotoxic effect on the cells, such as 336 below 100 uM. The individual peptides and Polymers were diluted in sodium acetate buffer and added to HUVECs in a 96-well plate. After incubating for a few days, the assay substrate was added and then incubated for a few hours at 37° C. Absorbance measurements were performed using a plate reader.

Referring now to FIG. 8 is shown HUVEC migration assays with 336 polymer/DEAH peptide (“DEAH” disclosed as SEQ ID NO: 2484). These nanoparticles inhibit endothelial migration in addition to proliferation and viability. Peptide-polymer nanoparticles were made as described previously. Samples were added to HUVEC cells and migration was measured using the ACEA time course cell migration system. Nanoparticle formulations at a total peptide concentration of 20 uM were able to inhibit migration more than any peptide only at 20 μM.

Referring now to FIG. 9 is shown in vivo 336 polymer nanoparticle/SP6001 DEAH peptide (“DEAH” disclosed as SEQ ID NO: 2484); Peptide-336 polymer nanoparticles were formulated as previously described and intravitreously injected to test in vivo efficacy. ACNV laser mouse model was used on C57 BL/6 female mice. The mice receive laser eye treatments on day zero, followed by the intravitreous injections. Mice are then perfused with fluorescein labeled dextran on day 14 and choroidal flat mounts (bottom) were analyzed via fluorescence microscopy. On day 14, both the peptide only and nanoparticles formulations significantly reduced angiogenesis in the eye (top) and did so to a similar extent. This suggests that all peptide was released from nanoparticles by day 14.

Referring now to FIG. 10 is shown (top) Particle size and (bottom) cell viability effects of various polymer/SP2012 nanoparticles as compared to peptide only of non-cytotoxic polymers; a range of polymer structures were mixed with SP2000 series peptides, in a similar manner as described above. Similar sizing is found with peptides from the same class with similar structural properties. For example, SP2000, SP2012, SP2024, SP2034, and SP2036 can be encapsulated similarly to each other with the same polymers, but different from peptides from other classes such as SP6001. Sizing was performed using the Malzern Zetasizer. Size strongly depends on polymer choice. Using the same cell viability assay as described previously, effects of nanoparticle vs. peptide only on HUVECs in a 96-well plate. Non-cytotoxic polymers are shown here. Referring once again to FIG. 10, the (top) panel suggests that some of these peptide-polymer formulations have an increased effect on HUVEC cell proliferation and viability (y-axis ratio less than one) as compared to peptide only. (Data also are normalized to any polymer-only effects. Pep-pol/pol/SP2012 refers to the change in cell proliferation/viability due to the peptide/polymer nanoparticle formulation divided by any change in cell proliferation/viability from the same dose of polymer by itself and this quantity divided by the change in cell proliferation/viability by delivering the same amount of peptide SP2012 as a bolus);

FIG. 11 shows polymer/peptide formulations for alternative peptides. Peptide-polymer formulations made as described previously. Here two different classes of peptides are used. Experiments performed in a 96-well plate, with final results obtained using the same cell viability/proliferation assay as described previously. An increased effect (decreased metabolic activity) is observed for the nanoparticle formulations over the free peptide.

Example 3 Hydrogels for Protein/Peptide Release

As shown in FIG. 12, FITC-tagged bovine serum albumin (BSA) was mixed with a macromer solution containing 10% (w/v) PEGDA (Mn-270 Da) with various amounts of B4S4, dissolved in a 1:1 (v/v) mixture of DMSO and PBS. Irgacure 2959 was added at 0.05% (w/v), and the solution was briefly vortexed and immediately polymerized to form gels. The gels were incubated at 37° C. in 1×PBS with shaking. PBS was removed at each time point to measure fluorescence.

The observed slowed release is due to two factors: first, increased overall hydrophobicity can decrease the movement of water in and out of the gel, reducing degradation rate and protein release. Furthermore, this method of mixing relatively hydrophobic diacrylates with hydrophilic diacrylates in a co-solvent (mixture of water and DMSO) that can dissolve both types of polymer causes the spontaneous formation of micro-emulsions within the gel (see SEM in FIG. 13; increasing B4S4 from top [0.2% w/w] to bottom [5% w/w]). Similar to traditionally studied controlled-release microparticles, these microparticles within photopolymerized gels could serve as another way to tune the release of an encapsulated peptide, protein, or drug.

Example 4 Stable Formulations

In this formulation nanoparticles were formed by mixing PBAE and DNA in 25 mM sodium acetate buffer (pH 5) at a 30:1 polymer:DNA ratio (w/w). After 10 min of incubation, sucrose solution was added at various concentrations. The particles were mixed, then frozen at −80° C. for 1 hr and lyophilized for 48 hr. They then were used for transfection or sizing or were stored at either room temperature, 4° C. or −20° C. and tested at various timepoints.

Referring now to FIG. 14, the size distribution of appropriately freeze-dried particles (bottom left, right-most histogram) remains the same as freshly-prepared particles (bottom left, left-most histogram). Freeze-dried particles also remain more stable in serum-containing medium than freshly-prepared particles (upper left). Using DNA-loaded nanoparticles, transfection efficiency is comparable between fresh particles and particles lyophilized with sucrose (right) even after 3 months of storage. Modifying type of sugar and concentration of sugar modulates the stability of the degradable nanoparticles.

Example 5 Inclusion of Lyophilized Nanoparticles into Pellets/Scaffolds

For coating of natural or pre-made synthetic scaffolds, DNA nanoparticles were prepared by mixing DNA and polymer in a sodium acetate buffer. Sucrose was added for a final concentration of 15 mg/mL, and the solution was used to coat the surface of a trabecular bone construct. This construct was then lyophilized for 2 days before being seeded with primary human cells (˜50% GFP⁺ for ease of visualization). Referring now to FIG. 15, DsRed expression was observed within 24 hr, indicating that the nanoparticles remained functional and able to transfect cells in this new system.

Lyophilized nanoparticles also can be mixed with PLGA microparticles to form a larger construct that can be more easily manipulated and also can tune controlled release properties. In this embodiment, DsRed DNA-containing nanoparticles were compressed into a pellet with PLGA microparticles. This pellet was then placed within a well containing primary human glioblastoma cells (˜20% GFP⁺ for ease of visualization through the opaque pellet). Referring now to FIG. 16, DsRed expression was observed within 4 days and remained very robust even after 12 days. Referring once again to FIG. 16, top=1 day, middle=4 days, bottom=12 days after transfection.

Further, as demonstrated in FIG. 17, DNA-loaded nanoparticles have been incorporated into natural and synthetic scaffolds, disks, microparticles, and hydrogels.

Example 6 Bioreducible Polymeric Particle Formulations for Delivery of siRNA

Reducible functional groups mediate successful siRNA-delivery, including transfection. In this example, GFP⁺ primary human glioblastoma cells were seeded in 96-well plates at a density of 10⁴ cells/well in complete culture medium (DMEM/F-12 with 10% FBS and 1% antibiotic-antimycotic) and allowed to adhere overnight. Just before transfection, the culture medium was changed to serum-free medium. Particles were prepared by diluting polymer and siRNA both in 25 mM sodium acetate buffer (pH 5), then mixing them at a 100:1 polymer:siRNA ratio (w/w). Nanoparticles formed spontaneously after 10 min of incubation and were added to the cells in medium at a 1:5 ratio (v/v) and a final concentration of 60 nM. Each polymer/siRNA treatment group was paired with a control group using a scrambled siRNA sequence (scrRNA). Cells were incubated with the particles for 4 hr. The medium and particles were then aspirated and replaced with complete medium. On each of the following days, GFP expression was measured using a Synergy 2 multiplate fluorescence reader (Biotek). Background fluorescence was measured from GFP-cells in medium and was subtracted from all other readings. Knockdown was calculated by normalizing GFP fluorescence (excitation 485 nm, emission 528 nm) from the siRNA-treated cells to the scrRNA-treated cells. Medium was changed every 3 days.

The reducible disulfide bond in the endgroup E10 (cystamine dihydrochloride) drastically improves siRNA delivery and gene knockdown. Referring now to FIG. 18, GFP⁺ glioblastoma cells were transfected with scrambled (control) siRNA (top panels) or siRNA against GFP (bottom). The polymers used as transfection agents consisted of B3-S5 at a 1.1:1 molar ratio, endcapped with (from left to right) E10, E3 (1,3=diaminopentane), or E6 (2-(3-aminopropylamino)ethanol). With the endgroups tested, the base polymer B3-S5 was able to achieve up to 8% knockdown; with E10 as the endgroup, over 80% knockdown was observed.

Referring now to FIG. 19A-FIG. 19C, the activity of R6-series polymers at delivering siRNA to knockdown GFP signal is GB cells is further demonstrated. % Knockdown of GFP expression in GFP⁺ glioblastoma cells transfected with siRNA against GFP, normalized to cells transfected with scrambled siRNA, using various BR6 polymers as a transfection agent. (A) Transfection with acrylate-terminated BR6 polymers with either S3, S4 or S5 as the side chain; (B) Transfection with E10 end-capped versions of the polymers in Figure A; and (C) GFP fluorescence images of cells transfected with BR6-S4-Ac complexed scrambled RNA (top) vs. siRNA against GFP (bottom);

Without wishing to be bound to any one particular theory, it is likely that E10 facilitates siRNA delivery by augmenting intracellular release because it degrades in the reducing intracellular environment. Results from gel retardation assay supports this hypothesis. Gel retardation assays were carried out by adding polymer of varying concentrations in sodium acetate buffer to a constant concentration of siRNA in sodium acetate. After 10 min of incubation, a solution of 30% glycerol in water was added at a 1:5 volumetric ratio as a loading buffer. Bromophenol blue or other dyes were not added, as they were found to interfere with binding. Samples were loaded into a 1% agarose gel with 1 g/mL ethidium bromide at 125 ng siRNA per well. Samples were run for 15 min under 100 V, then visualized using UV exposure.

Referring now to FIG. 20, a gel retardation assay of siRNA with BR6-S5-E10 at varying ratios of polymer to RNA is shown. The polymer effectively retards siRNA (top), but in the presence of 5 mM glutathione siRNA is released immediately (bottom). These data demonstrate the hypothesized intracellular release of siRNA and elucidates the mechanism by which nanoparticles formed using BR6 facilitate strong siRNA transfection and GFP knockdown.

Referring also to FIG. 21, an E10-endcapped polymer (top) retards siRNA efficiently, but upon addition of 5 mM glutathione, siRNA is immediately released (bottom). Numbers refer to the w/w ratio of polymer-to-siRNA in all cases.

Referring now to FIG. 22, the same polymer as in FIG. 21, but with a different endcap (E7, 1-(3-aminopropyl)-4-methylpiperazine) also retards siRNA (top), but is not affected by application of glutathione (bottom).

Referring now to FIG. 23, gel permeation chromatography data of BR6 polymerized with S4 at a BR6:S4 ratio of 1.2:1 at 90° C. for 24 hours, before and after end-capping with E7, are provided.

Referring now to FIG. 24, knockdown efficiency also is affected by molecular weight of the polymer. In FIG. 24, 1.2:1, 1.1:1, and 1.05:1 refer to the ratio of reactants in the base polymer step growth reaction, which affects the ultimate molecular weight. Top 4310 formulations were able to achieve greater knockdown over time compared to commercially available reagents like Lipofectamine 2000 (Lipo).

Referring now to FIG. 25, combined DNA (RFP) and siRNA delivery (against GFP) in GB; GFP⁺ GB cells were treated with scrambled siRNA (top) or siRNA against GFP (bottom), causing visible knockdown. Interestingly, different polymer structures seem ideal for siRNA versus DNA delivery or for both. One polymer effective in both was used to deliver both siRNA against GFP and plasmid DsRed DNA to GFP⁺ hMSCs, resulting in the ability to turn green cells red.

Referring now to FIG. 26, siRNA knockdown is affected by the endcap (E), base polymer (increasing hydrophobicity from L to R within each E), and molecular weight (increasing L to R within each base polymer). One endcap that shows high knockdown even at lower molecular weights is E10, which is strikingly more effective than the other endcaps tested for the same base polymers. Other PBAEs were also highly effective when synthesized at high molecular weight.

Referring now to FIG. 27, is shown 4410, 200 w/w (blue line on above graph), 8 days after transfection: Left: hMSCs treated with scrambled control; Right: hMSCs treated with siRNA.

Referring now to FIG. 28, in some embodiments, polymer molecular weight is between 4.00-10.00 kDa for siRNA delivery.

Example 7 DNA Delivery

Referring now to FIG. 29, the presently disclosed biomaterial can be used for other forms of delivery, for example DNA delivery. DNA transfection shows some similar trends compared with siRNA, but with different optimal endcaps. Specific polymer structure is critical to determine which polymers are effective for DNA delivery or siRNA delivery or both. Both DNA and siRNA transfection depend less on MW with high polymer hydrophobicity. High GFP DNA delivery was achieved using PBAEs, with transfection in 10% serum and at 5 g DNA/mL. Referring now to FIG. 30, several formulations with up to 90% transfection and high (>90%) viability are shown.

Referring now to FIG. 31, GB transfection is demonstrated. More particularly, 551 GB cells cultured as neurospheres (undifferentiated). They were plated in monolayer on laminin 24 hr before transfection with DsRed DNA using 447 LG (red). 48 hr after transfection, they were stained for nestin (blue). Red and blue overlaid (left) show that transfection occurred in nestin+ cells (nestin only: right).

Referring now to FIG. 32, for a DNA delivery application, in some embodiments, polymer molecular weight is between 3.00-10.0 kDa.

Example 8 In Vivo Activity for Selected Peptides

In some embodiments, the presently disclosed subject matter demonstrates in vivo activity for selected peptides in DIVAA angioreactors and a lung cancer xenograft model, Koskimaki J E, Karagiannis E D, Tang B C, Hammers H, Watkins D N, Pili R, et al. Pentastatin-1, a collagen IV derived 20-mer peptide, suppresses tumor growth in a small cell lung cancer xenograft model. BMC Cancer 2010; 10:29, and in a breast cancer xenograft model using MDA-MB-231 cells. Koskimaki J E, Karagiannis E D, Rosca E V, Vesuna F, Winnard P T, Jr., Raman V, et al. Peptides derived from type IV collagen, CXC chemokines, and thrombospondin-1 domain-containing proteins inhibit neovascularization and suppress tumor growth in MDA-MB-231 breast cancer xenografts. Neoplasia 2009; 11(12):1285-91.

Following orthotopic inoculation of SCID mice in the mammary fat pad area using 2×10⁶ cells, tumors grew to approximately 100 mm³ in 2 weeks; at that time 100 L of peptide solution was injected i.p. once a day at peptide doses 10-20 mg/kg. PBS solution was injected as control. Several peptides have been found to inhibit tumor growth. See FIG. 33A. The microvessel density was determined by screening the immunohistologically stained CD31 sections. Inhibition of LEC migration in the ACEA migration assay also was determined (see FIG. 33B).

Representative data showing the activity of free peptide and peptide encapsulated in the presently disclosed polymeric particles are shown in FIG. 33D, which shows the metabolic activity of free peptides and peptides in polymeric particles.

Example 9 Non-Viral Gene Delivery for Treatment of Glioblastoma and Brain Cancer Stem Cells

Glioblastoma (GB) is a grade IV brain cancer as defined by the WHO and is the most common primary CNS tumor in the United States. Current treatment includes surgical resection, radiotherapy, and chemotherapy. The median survival with treatment is approximately 14 months.

Brain cancer stem cells (BCSCs) possess genetic and morphological features similar to neural stem cells. Small numbers of BCSCs can initiate gliomas. BCSCs are refactory to conventional anti-cancer treatments.

Gene delivery typically is accomplished by either vaccine-mediated or polymer mediates techniques. Virus-mediated gene delivery is highly efficient, insertional mutagenesis, and toxicity/immunogenicity. Polymer-mediated gene delivery is chemically versatile, potentially safer than vaccine-mediated gene delivery, but typically is less efficient. See Green et al., 2008. Acc. Chem. Res. 41(6):749-59; Putnam 2006. Nat. Mater. 5(6):439-51.

Non-viral, e.g., polymer-mediated gene delivery, can be accomplished, in some embodiments, by using poly(beta-amino esters) (PBAEs). In particular embodiments, PBAEs suitable for use in target delivery can be synthesized in a two-step reaction provided herein below in Scheme 6 and can form nanocomplexes with negatively-charged cargo (e.g., DNA, siRNA) via electrostatic interactions as disclosed, for example, in some embodiments described in International PCT Patent Application Publication No. WO/2010/132879 for “Multicomponent Degradable Cationic Polymers,” to Green et al., which is incorporated herein by reference in its entirety.

In some embodiments, the presently disclosed subject matter demonstrates the delivery of DNA to GB cells, i.e., bulk tumor (non-stem cells; verifies the efficacy of the presently disclosed methods in BCSCs; demonstrates the delivery of apoptosis-inducing genes in BCSCs; provides practical considerations for translation of the presently disclosed methods; and discusses how the presently disclosed methods can be used in conjunction with other methods for treating GB.

The delivery of DNA to GB cells, bulk tumor (non-stem cells) and the efficacy of the presently disclosed methods to deliver DNA to BCSCs is demonstrated in FIG. 36-FIG. 39.

Referring now to FIG. 34, the delivery of DNA to GB bulk tumor cells is demonstrated for representative biomaterials. Referring now to FIG. 35, the transfection of genes to BCSC is demonstrated for representative presently disclosed biomaterials. FIG. 36 demonstrates the delivery of DNA to fetal (healthy) cells. FIG. 37 also demonstrates the delivery of DNA to BCSCs. The delivery of apoptosis-inducing genes in BCSCs is demonstrated in FIG. 38 to FIG. 39.

These data demonstrate that PBAEs can be used for highly effective DNA delivery to GB cells, including tumor-initiating stem cells; transfection occurs even in 3D neurospheres in suspension; transfection is much less efficient in non-cancer cells (F34 fetal cells) as compared to GB cells; and transfection with secreted TRAIL causes more death in BCSCs with not significant effect on healthy cells.

In practical considerations for translation, for lyophilized nanoparticles, the presently disclosed methods provide an ease of preparation, e.g., only water needs to be added to the lyophilized nanoparticles, long-term storage, large, consistent batches, manipulation for uses in other devices, and stability in suspension. See scheme in FIG. 3.

As shown in FIG. 40, particles lyophilized with sucrose and used immediately are as effective in transfection as freshly prepared particles. Further, no loss in efficiency is observed within three months; and approximately 50% efficiency is retained after six months. The use of the presently disclosed materials and methods for long-term gene delivery is demonstrated in FIG. 41 and FIG. 42. Other methods for treatment of GB include siRNA delivery to GB cells (FIG. 43).

A comparison of siRNA vs. DNA delivery in GB cells is shown in FIG. 44 and FIG. 45. More particularly, as shown in FIG. 45, both 4410 and 447 can form complexes with DNA and siRNA; a higher weight ratio of polymer-to-nucleic acid is needed for siRNA than for DNA; E10 polymers release siRNA immediately, but not DNA, upon addition of glutathione (GSH).

In summary, PBAE/nucleic acid nanoparticles can be fabricated in a form that remains stable over time and allow flexibility for clinical use; PBAEs can be used for effective DNA or siRNA delivery to GB-derived BCSCs; and efficient release of cargo is necessary for effective nucleic acid delivery, especially with siRNA.

Example 10 Microparticles for Peptide Delivery

In some embodiments, microparticles for controlled release of nanoparticles, which themselves encapsulate biological agents, are illustrated in FIG. 14-FIG. 17.

More particularly, FIG. 46 depicts a strategy of combining nanoparticles within microparticles to extend release further. PLGA or blends of PLGA can be combined with the presently disclosed polymers to form microparticles by double emulsion. FIG. 47 shows release of a representative peptide, DEAH-FITC (“DEAH” disclosed as SEQ ID NO: 2484), from a presently disclosed microparticle. FIG. 48 shows slow extended release from microparticles containing nanoparticles that contain peptides; FITC-DEAH (“DEAH” disclosed as SEQ ID NO: 2484) peptide was first mixed with the 336 PBAE to allow for self-assembly into nanoparticles and was then mixed with BSA (middle) or not (bottom) to form an aqueous mixture. This mixture was added to a DCM-PLGA phase and sonicated to form a w/o suspension. This suspension was then added to a PVA solution and homogenized to form the final w/o/w suspension. This mixture was finally added to another PVA solution to allow for the DCM to evaporate and harden the formed microparticle. Different release profiles can potentially be obtained as seen above for the different microparticle formulations. In all cases, there is a long-term release of the peptide. Forming nanoparticles that encapsulate the peptide within the microparticles, extends the release compared to encapsulating peptide directly into microparticles (middle figure). The particles can be designed to have different release depending on the local environment (top figure). In some embodiments, release is constant over time and zero-order with respect to time (bottom figure).

Referring now to FIG. 49 in shown the in vivo effects of microparticle formulations in both the CNV and rho/VEGF model over time. DEAH (SP6001)-336 PBAE nanoparticle formulation made as described previously (“DEAH” disclosed as SEQ ID NO: 2484). (Top) Intravitreal injections into CNV model mice as described previously show comparable effects after 14 days, even though only small fraction of peptide is released over that time from microparticles. (Middle) and (Bottom) A genetic model of wet form of age-related macular degeneration in mice used to test long-term effect of microparticles. After 1 week (middle) comparable effects seen in reduction of angiogenesis. After 8 weeks (bottom), however, while peptide only no longer inhibits angiogenesis, the microparticle still does, as it is still releasing peptide over this time. While PLGA is used to form the microparticles used above, other polymers may be used including the synthetic polyesters and polyamides described above. In certain embodiments, blends of these polymer are combined with PLGA to form microparticles with differing environmental sensitivity and release properties; (a) the effect of microparticle (SP-6001) in CNV model mouse; (b) the effect of microparticle (SP-6001) in rho/VEGF (V6) mouse, 1 week after injection; and (c) the effect of microparticle (SP-6001) in rho/VEGF (V6) mouse, 8 weeks after injection.

REFERENCES

All publications, patent applications, patents, and other references mentioned in the specification are indicative of the level of those skilled in the art to which the presently disclosed subject matter pertains. All publications, patent applications, patents, and other references are herein incorporated by reference to the same extent as if each individual publication, patent application, patent, and other reference was specifically and individually indicated to be incorporated by reference. It will be understood that, although a number of patent applications, patents, and other references are referred to herein, such reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art.

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Although the foregoing subject matter has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be understood by those skilled in the art that certain changes and modifications can be practiced within the scope of the appended claims. 

1-13. (canceled)
 14. The nanoparticle, microparticle, or gel of claim 15, wherein the nucleic acid is an siRNA or a combination of siRNA.
 15. The nanoparticle, microparticle, or gel of claim 16, wherein the nucleic acid is selected from the group consisting of a gene, DNA, RNA, siRNA, miRNA, isRNA, agRNA, smRNA, and combinations thereof.
 16. A nanoparticle, microparticle, or gel comprising a compound of formula (I):

wherein: n is an integer from 1 to 10,000; R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, and R₉ are each independently selected from the group consisting of hydrogen, branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, aryl, halogen, hydroxyl, alkoxy, carbamoyl, carboxyl ester, carbonyldioxyl, amide, thiohydroxyl, alkylthioether, amino, alkylamino, dialkylamino, trialkylamino, cyano, ureido, a substituted alkanoyl group, cyclic, cyclic aromatic, heterocyclic, and aromatic heterocyclic groups, each of which may be substituted with at least one substituent selected from the group consisting of branched or unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, amino, alkylamino, dialkylamino, trialkylamino, aryl, ureido, heterocyclic, aromatic heterocyclic, cyclic, aromatic cyclic, halogen, hydroxyl, alkoxy, cyano, amide, carbamoyl, carboxylic acid, ester, carbonyl, carbonyldioxyl, alkylthioether, and thiohydroxyl groups; wherein R₁ can be present or absent and when present the compound of formula (I) further comprises a counter ion selected from the group consisting of chloride, fluoride, bromide, iodide, sulfate, nitrate, fumarate, acetate, carbonate, stearate, laurate, and oleate; and at least one of R, R′, and R″ comprise a reducible or degradable linkage, and wherein each R, R′, or R″ can independently be the same or different; under the proviso that when at least one R group comprises an ester linkage of the formula —C(═O)—O— and the compound of formula (I) comprises a poly(beta-amino ester), then the compound of formula (I) must also comprise one or more of the following characteristics: (a) each R group is different; (b) each R″ group is different; (c) each R″ group is not the same as any of R′, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, and R₉; (d) the R″ groups degrade through a different mechanism than the ester-containing R groups, wherein the degradation of the R″ group is selected from the group consisting of a bioreducible mechanism or an enzymatically degradable mechanism; and/or (e) the compound of formula (I) comprises a substructure of a larger cross-linked polymer, wherein the larger cross-linked polymer comprises different properties from compound of formula (I); wherein R comprises a backbone of a diacrylate selected from the group consisting of:

and one or more nucleic acids.
 17. The nanoparticle, microparticle, or gel of claim 16, wherein n is an integer selected from the group consisting of from 1 to 1,000, from 1 to 100, from 1 to 30, from 5 to 20, from 10 to 15, and from 1 to
 10. 18-22. (canceled)
 23. The nanoparticle, microparticle, or gel of claim 16, wherein the reducible or degradable linkage comprising R, R′, and R″ is selected from the group consisting of an ester, a disulfide, an amide, an anhydride or a linkage susceptible to enzymatic degradation, subject to the proviso of claim
 16. 24. (canceled)
 25. The nanoparticle, microparticle, or gel of claim 16, wherein R′ comprises a side chain derived from compound selected from the group consisting of:


26. The nanoparticle, microparticle, or gel of claim 16, wherein R″ comprises an end group derived from a compound selected from the group consisting of

27-65. (canceled)
 66. A method of treating a disease or condition, the method comprising administering to a subject in need of treatment thereof a therapeutically effective amount of a nanoparticle, microparticle, gel, or multilayer particle of claim 16, wherein the nanoparticle, microparticle, gel, or multilayer particle further comprises a nucleic acid specific for the disease or condition to be treated.
 67. The method of claim 66, wherein the disease or condition comprises an angiogenesis-dependent disease or condition.
 68. The method of claim 67, wherein the angiogenesis disease or condition is selected from the group consisting of a cancer and age-related macular degeneration.
 69. The method of claim 66, wherein the disease or condition is a non-angiogenic disease or condition.
 70. The method of claim 66, wherein the nucleic acid is selected from the group consisting of gene, DNA, RNA, siRNA, miRNA, isRNA, agRNA, smRNA, and combinations thereof. 